Professor Ron Davis's response to Naviaux study, including Q and A with Dr Naviaux

[Sasha]

Apologies if this is a stupid question but there are many of us who have gone through a lengthy period of relapsing /remitting illness wholly independent of PEM, although that would also sometimes be present.

In such cases would it be expected that the tested metabolites would appear different depending on the patients' state at the time samples were taken? Have tests been done on samples from patients over a period and do they show variation?

In the paper, it said that "metabolites were correlated with the clinical severity of CFS" (p. 3) so I think the answer would be, yes, your results will vary as your health varies.

 

[alex3619]

I personally think that the disease is present in some subclinical form before the trigger, and that the trigger is probably a red herring. In my case there was no trigger. Already years before there were some subtle warning signs that something in the body was abnormal but that had essentially no impact on functioning, so it was ignored.

I discussed something similar that I called the Two Hit Hypothesis in the early 2000s. It went down like a lead balloon. Though of course it could be a multiple hit issue too. I would not describe my onset as sudden or slow, it was staged. Each severe infection etc. drove me down step by step.

 

[user9876]

In the paper, it said that "metabolites were correlated with the clinical severity of CFS" (p. 3) so I think the answer would be, yes, your results will vary as your health varies.

I wonder whether the metabolites that are effected change as health and symptoms change. Or whether it is always the same metabolites that are different but the degree of difference changes with severity. I think to get to this type of question a longitudinal study would need to be done (i.e. looking at a few patients over a long time).

 

[Ben H]

Apologies if this is a stupid question but there are many of us who have gone through a lengthy period of relapsing /remitting illness wholly independent of PEM, although that would also sometimes be present.

In such cases would it be expected that the tested metabolites would appear different depending on the patients' state at the time samples were taken? Have tests been done on samples from patients over a period and do they show variation?

Not a stupid question at all @Chrisb.

Like Sasha has said, and was shown in the study, metabolites correlated with clinical severity.

I think it very plausible that metabolites would differ in the stages or severity of the illness. Hopefully the 8/13 that provided a potential diagnostic marker would still be there, but perhaps the amount of metabolites available would differ. It would make logical sense but we need to have it on paper.

The next stage (after the replication for which samples have been collected) is to test this against moderately ill patients and see if the same metabolomic markers (of which 94% and 96% sensitivity could identify male and females with ME/CFS respectively in the study) are there. This would help with your question. But this still needs FUNDING!

A study on the same patients, using metabolomics, through various stages of the illness would be very interesting indeed. But we need much more funding.

Great question!


B

 

[Sasha]

My brain's bouncing around too much today to go looking for this - but can someone tell me, were the key metabolites that would form the diagnostic group all present in the blood? Or (if this is confirmed) would tests also need to be done on other kinds of samples (urine, saliva, stool, etc.)?

 

[alex3619]

My brain's bouncing around too much today to go looking for this - but can someone tell me, were the key metabolites that would form the diagnostic group all present in the blood? Or (if this is confirmed) would tests also need to be done on other kinds of samples (urine, saliva, stool, etc.)?

Yes, they were all in the blood. However that does not mean that additional markers could not be found elsewhere. Blood tests are generally considered convenient ... and much safer than things like spinal fluid.

 

[Sasha]

@Ben Howell - I don't know if this is the appropriate thread for you to send questions to the OMF about this study (or to Dr. Naviaux, given that it wasn't an OMF study), but, going forward, I can see a lot of PWME being keen to have their blood analysed by Metabolon (or whoever else can do this stuff in our various countries).

It would make tons of sense and presumably speed research up considerably if we shared our data with the OMF/Naviaux. I can imagine people being willing to pay to get genetic testing, too.

Is anybody at OMF/Naviaux's lab thinking about this?

 

[Sasha]

And, @Ben Howell - if you're collecting questions! - I'd like to ask what clinical speciality patients should now be seeking out. What kind of doctors can we go to who can do these tests, interpret the results, and use them as a basis to try to inform treatment? If a lot of this is going to need to be personalised medicine (the "75%") rather than the common cure (the "25%"), there's no point waiting for clinical trials.

 

[Forbin]

So now there are two studies showing that two different things are stuck in the "on" position in ME/CFS:

The 2015 Lipkin/Hornig study of cytokines from the CII, and Dr. Naviaux's new metabolomics study out of UCSD.

One system is initially seen to be stuck in a "hyperimmune" state, while the other is stuck in hypometabolic state.

It would be pretty coincidental if these two persistent dysregulations were unrelated, so is one causing the other, are they mutually reinforcing or are they both caused/initiated by something else?

And could Dr. Nath's study potentially confirm these findings?

And what does Canadian Committee Member 1 think about all this?

 

[Sasha]

Another question, @Ben Howell (sorry to keep bugging you!). Are OMF/Naviaux planning anything to answer our actual questions? It would be fantastic if they did. They've done their best to anticipate the main ones with their Q&A document but now we're in a new phase where patients have lots of specific questions and it would be great to get some answers, even if it's just "We don't know".

 

[snowathlete]

I discussed something similar that I called the Two Hit Hypothesis in the early 2000s. It went down like a lead balloon. Though of course it could be a multiple hit issue too. I would not describe my onset as sudden or slow, it was staged. Each severe infection etc. drove me down step by step.

I had a similar experience. In my case, I'd say after each infection I recovered partially, but not fully. So each time the signal built up, and/or the potential for the signal, it's sensitivity, built up. As I got more sick, other things seemed to trigger that state too, exercise certainly; the first time I knew I was in serious trouble was after a swimming session. I felt more exhausted than normal afterwards and when I got home I just collapsed.

 

[alex3619]

other things seemed to trigger that state too, exercise certainly

Exercise did it to me too, though not as severely as infection, except for moving house. Each time I do that my health goes down further.

 

[alex3619]

there's no point waiting for clinical trials.

The availability of the technology and doctors able to interpret the results are likely to be a big issue. There is a also the question as to how much of the personalized abnormailites are due to the core problems. We just don't know yet, but that does not mean we shouldn't try to do things to fix the issues.

 

[trishrhymes]

''It would make tons of sense and presumably speed research up considerably if we shared our data with the OMF/Naviaux. I can imagine people being willing to pay to get genetic testing, too''.

I guess it would depend why one would get the testing done at this stage.

Would it make more sense for individuals who want

a) confirmation of diagnosis, or

b) details of what their own profile shows and advice on what treatment to use as a result or

c) to contribute data to the research

to wait a little.

a) I gather from what I've read that they are working on developing a diagnostic test, so better to wait for this, which is likely to be cheaper and have a stronger evidence base once the confirmatory study with more patients has been completed.

b) it's too early, the treatments haven't been developed yet, nor the specifics of what each individual's metabolome means - asking for help individually would distract busy researchers from getting on with work that can help everyone, and these researchers are, as far as I know, scientists, not clinicians.

c) Loading a study with self-selecting patients who can afford to pay could distort proper scientific sampling.

I guess what I'm saying is, we need to be patient.

I suspect the best thing we can do if we have money to spare is donate it to the OMF so they can continue to do research that will help all of us. Now is not the time to ask for individual help and advice.

But I'm so thrilled and grateful for what is being done on all our behalf, and I completely understand that we all want to be involved and desperate people want to focus on their own individual needs. It's hard being patient!

 

[Ben H]

@Ben Howell - I don't know if this is the appropriate thread for you to send questions to the OMF about this study (or to Dr. Naviaux, given that it wasn't an OMF study), but, going forward, I can see a lot of PWME being keen to have their blood analysed by Metabolon (or whoever else can do this stuff in our various countries).

It would make tons of sense and presumably speed research up considerably if we shared our data with the OMF/Naviaux. I can imagine people being willing to pay to get genetic testing, too.

Is anybody at OMF/Naviaux's lab thinking about this?

And, @Ben Howell - if you're collecting questions! - I'd like to ask what clinical speciality patients should now be seeking out. What kind of doctors can we go to who can do these tests, interpret the results, and use them as a basis to try to inform treatment? If a lot of this is going to need to be personalised medicine (the "75%") rather than the common cure (the "25%"), there's no point waiting for clinical trials.

Another question, @Ben Howell (sorry to keep bugging you!). Are OMF/Naviaux planning anything to answer our actual questions? It would be fantastic if they did. They've done their best to anticipate the main ones with their Q&A document but now we're in a new phase where patients have lots of specific questions and it would be great to get some answers, even if it's just "We don't know".

Hey Sasha,

I am collecting questions so all good

Metabolomics should be rolled out fairly soon for patients. I am working on this with the person involved-particulary the UK side of things. @Rose49 is well informed of all this.

That will be beneficial for both patients and researchers for some of the reasons you mentioned.

Inplications for treatment are hinted at, but as Naviaux said this was not a 'treatment' study-though they are working on that side of things.

Yes OMF/Naviaux are going to answer these questions-we are very lucky! Direct input from researchers of this calibre is very fortunate, and kind. They really do have limited time as they are producing this kind of groundbreaking research, and working everyday for us!


B

 

[msf]

Ben, I have a question, but it´s for you rather than the researchers, as I´m sure you´ll know the answer:

Are OMI in communication with Lipkin and his group, or Montoya and his group? They seem to overlap to a certain extent in terms of their research areas. Is this a case of competition or collaboration (not saying either is better, just curious to know what the situation is)?

 

[Sasha]

I suspect the best thing we can do if we have money to spare is donate it to the OMF so they can continue to do research that will help all of us. Now is not the time to ask for individual help and advice.

I think you misunderstand me - I don't want to ask (or have others ask) OMF/Naviaux for individual advice. I want to know what kind of specialists in our local hospitals would know enough to interpret these tests and to be able to tackle some of the problems that they reveal.

 

[bel canto]

"Direct input from researchers of this calibre is very fortunate, and kind"

Amazing to have this kind of access for answers to our questions. Please, Ben, tell them how immensely grateful we are, not only for the research, but for their kindness.

 

[Sasha]

c) Loading a study with self-selecting patients who can afford to pay could distort proper scientific sampling.

Patients are always self-selecting, even in a clinical trial. I accept your point about bias but I think the selection is likely to be on the basis of who's sickest, mostly, and I don't think that's a bad thing. And overall, it's a question of trade-off - better to have a large, self-funding, but biased sample, or a non-existent/small one, still with its own biases?

 

[Hutan]

I personally think that the disease is present in some subclinical form before the trigger, and that the trigger is probably a red herring. In my case there was no trigger. Already years before there were some subtle warning signs that something in the body was abnormal but that had essentially no impact on functioning, so it was ignored.

It is very possible that I and my two children had some symptoms prior to the time that we clearly became ill.

But the descent in to illness was so rapid and marked and synchronised in the three of us that I feel sure that there was a trigger or combination of triggers. Classic Ramsey ME was described in outbreaks - it is unlikely that so many people becoming ill with the same symptoms were just coincidences.

Just prior to becoming ill, we were in our house with our personal goods newly arrived from a country where pesticide controls are poor. The fumigant was methyl bromide and fumes of hydrogen sulphide created by that fumigant reacting with sulphur in things like wool, feather pillows and foam rubber in mattresses were very very strong for days. This was compounded by the fact that there was a severe and unusual heatwave with temperatures over 40 degrees Celsius for a week. Our brick house with no air conditioning became like an oven. Soon after that we all had a gastric flu - and then ME. My husband was overseas and wasn't exposed to the fumes or the virus and didn't get ME.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2154480/

Mice exposed to H2S enter into a physiological state that allows them to endure periods of low metabolic rate and decreased core body temperature without apparent ill effects (6). The H2S-induced state also allows for mice to survive exposure to otherwise lethal hypoxic conditions (7). In rats, H2S improves outcome after severe hemorrhage (50). These studies raise the possibility that exogenous H2S could be of clinical benefit, especially for pathologies resulting from decreased oxygen perfusion.

Roth’s hibernation research made headlines worldwide in April 2005 when he was the first to show that exposing mice to minute amounts of hydrogen sulfide could induce a state of reversible “hibernation on demand,” dramatically reducing their core body temperature, respiration and need for oxygen. Roth envisions a future in which similar techniques could be used to “buy time” for critically ill patients who otherwise would face injury and death from insufficient blood and oxygen supply to organs and tissues.

Roth hypothesizes that H2S, a chemical normally produced in humans and animals, may help regulate body temperature and metabolic activity. Hydrogen sulfide is similar to oxygen at the molecular level because it binds at many of the same proteins. As a result, H2S competes for and interferes with the body’s ability to use oxygen for energy production – a process within the cell’s power-generating machinery called oxidative phosphorylation.

The inhibition of this function, in turn, is what Roth and colleagues believe causes organisms such as mice to shut down metabolically and enter a hibernation-like state pending re-exposure to normal room air, after which they quickly regain normal function and metabolic activity with no long-term negative effects.
Read more at: http://phys.org/news/2007-12-hydrogen-sulfide-key-life.html#jCp