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Dry eye syndrome and the subsequent risk of CFS - a prospective population-based study

Wonkmonk

Senior Member
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1,006
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Germany
I'm convinced its some sort of persistent pathogen with inflammation driven by the immunological process causing the issue. The only thing I can put a finger on was a primary herpes infection.

This sounds interesting, because my CFS is also suspected to be caused by herpes virus. And I have unexplained HSV-1 IgG titers 1:32,000.

I also think there is a connection.
 

used_to_race

Senior Member
Messages
193
Location
Southern California
This sounds interesting, because my CFS is also suspected to be caused by herpes virus. And I have unexplained HSV-1 IgG titers 1:32,000.

I also think there is a connection.

Have there been any studies on herpesvirus titers in healthy people? I tried to do a quick literature search and didn't find anything super relevant. I found a few papers that show a correlation between high VCA IgG titers and a variety of diseases, ranging from MS to RA to Nasopharyngeal Carcinoma. Sometimes the researchers imply that they think there's a causal relationship one way or the other, but we just don't know enough about these viruses or the immune system to say. I think any immune-mediated disease could be likely to upregulate production of antibodies.

Even if people with, say, ME/CFS produce more EBV/HSV antibodies than healthy controls, how does that show anything about what's causing symptoms? Most people don't have viremia by PCR, and I think at this point even the ME/CFS researchers are skeptical that there's some kind of "intracellular" or "tissue-localized" infection in most ME/CFS patients. We will have to see what the current wave of Stanford studies ends up showing. They are looking at cytokines and T cell activation, which should tell us a lot about the nature of immune activation in ME/CFS. I have a feeling the metabolic angle is what will produce results in the longer (or hopefully shorter) term.

In the meantime, treatment for a lot of autoimmune diseases revolves around inducing remission with immunosuppressants or monoclonal antibodies, and then figuring out a less toxic treatment to maintain the remission. This is my understanding of how things generally go for MS, Lupus, RA, Crohn's, etc etc. Perhaps antiviral therapy has a role to play in this but I think that for induction of remission we can all see that it's not very effective for most people. There will surely be clinical trials starting up for various immunosuppressants and biologics within the next 0-3 years, and I am optimistic we will find a workable solution for many subgroups of patients, at least to hold us over until we understand these diseases better.
 

Wonkmonk

Senior Member
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1,006
Location
Germany
Very interesting points. I have comments on some of them.

Have there been any studies on herpesvirus titers in healthy people? I tried to do a quick literature search and didn't find anything super relevant.

I know not, but 1:32,000 is definitely a very high level, though my doctor has told me of one patient who doesn't have any apparent illness and had a HSV-1 titer of 1:18,000 I believe. That makes her sceptical that it's actually herpes simplex.

I think any immune-mediated disease could be likely to upregulate production of antibodies.

Theoretically yes, but in my case, only HSV-1 is (massively) upregulated. All other titers, both bacteria (Mycoplasma pneumonia) and viruses (EBV, Influenza, HHV6) all have rather low titers. A dozen autoantibodies were also tested and they are absent.

So if anything else is upregulating antibody production, it would be hard to explain why only HSV-1 is upregulated.

Even if people with, say, ME/CFS produce more EBV/HSV antibodies than healthy controls, how does that show anything about what's causing symptoms? Most people don't have viremia by PCR?

I think Drs Lerner and Montoya have shown a (not entirely convincing) connection between high herpes virus titers and some response to antivirals against exactly these viruses. On the other hand, there is the Naviaux memo that as I read it pretty much rejects any connection between high herpesvirus titers and CFS.

Either way, because, as you say, viremia is absent, you need something like abortive or nonproductive intracellular infection to make the connection to the titers. This theory has never been proven, but as far as I know, it has also not been refuted.

Perhaps antiviral therapy has a role to play in this but I think that for induction of remission we can all see that it's not very effective for most people.

This is correct, but on the other hand if we take autoimmunity or an overactive immune system as a theory, we know how to suppress significant parts of the immune system quite effectively (corticosteroids, B-cell depletion, Methotrexate etc.) and the record seems as bleak as with antivirals. I do not think that route is more promising at this time.
 
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used_to_race

Senior Member
Messages
193
Location
Southern California
I know not, but 1:32,000 is definitely a very low level, though my doctor has told me of one patient who doesn't have any apparent illness and had a HSV-1 titer of 1:18,000 I believe. That makes her sceptical that it's actually herpes simplex.

I assume you mean high level and I would agree. I've had some pretty knowledgeable infectious disease and immunology specialists tell me they'll treat people for certain infections like CPn or VZV and see high titers for a long time afterwards though. There has to be a point at which it's concerning, however. I'm not sure where that point exists and if a person is able to maintain a healthy equilibrium with "high" titers then I wouldn't guess it's a problem. There haven't been any good studies done on this, and without context I'm afraid we are just speculating.

Theoretically yes, but in my case, only HSV-1 is (massively) upregulated. All other titers, both bacteria (Mycoplasma pneumonia) and viruses (EBV, Influenza, HHV6) all have rather low titers. A dozen autoantibodies were also tested and they are absent.

So if anything else is upregulating antibody production, it would be hard to explain why only HSV-1 is upregulated.

This is an interesting line of discussion but I am not knowledgeable enough about virology or immunology to really say why this could be. My guess is that, because we have evolved to keep herpes viruses in a latent state for long periods of time, our immune systems tend to produce antibodies to those viruses rather than other viruses to which most of us have been exposed. However there are other people who have had high titers to enteroviruses or parvovirus (or indeed CPn and MycoPn) for a long time. I would love to see a study on many ME/CFS patients attempting to correlate disease severity and antibody titers. I think Stanford is doing some HLA-DR genotyping that will shed some light on this type of thing to see if there is any pattern to be explored. My own illness is pretty mild and I don't have any especially high titers to any viruses.

I think Drs Lerner and Montoya have shown a (not entirely convincing) connection between high herpes virus titers and some response to antivirals against exactly these viruses. On the other hand, there is the Naviaux memo that as I read it pretty much rejects any connection between high herpesvirus titers and CFS.

Montoya's work on Valcyte is not really that impressive. Sure there are stories where it has helped people significantly and I am glad for those people but it is the exception rather than the rule. Lerner's numbers (like Chia's) seem too good to be true and his results have not been replicated. His proposed abortive infection model is (I think) complete speculation, but I'm fuzzy on the details and again I'm no expert. People have looked for active viral infections in ME/CFS and they have not found them for the most part. Which brings me back to the same point - if there is no active infection then we are better off treating the underlying immune dysfunction, but first we must understand what is going on. That is why I think that the current wave of studies is so important.

Naviaux is a very accomplished virologist as well as being a metabolomics expert and I would put more stock into what he says than some isolated infectious disease clinicians. I believed the stuff about Lerner, Chia, and Montoya for a while but I think it's just that part of human nature that wants an easy solution.

Either way, because, as you say, viremia is absent, you need something like abortive or nonproductive intracellular infection to make the connection to the titers. This theory has never been proven, but as far as I know, it has also not been refuted.

Something that can be asserted without evidence can also be dismissed without evidence.

This is correct, but on the other hand if we take autoimmunity or an overactive immune system as a theory, we know how to suppress significant parts of the immune system quite effectively (corticosteroids, B-cell depletion, Methotrexate etc.) and the record seems as bleak as with antivirals. I do not think that route is more promising at this time.

I disagree. The studies on Rituximab and Cyclophosphamide (although to be fair the RTX phase 3 has its problems and the cycloME is not yet published) have shown a lot of promise. There was also the paper on immunoadsorption + IVIg from Schiebenbogen that is exciting. Additionally we have heard anecdotes of drugs like corticosteroids, IVIg alone, and sirolimus/rapamune inducing remission or major improvement of symptoms. It is likely there are subgroups involved here and once we know more about this we will be able to find an effective immune-centric treatment for a large proportion of ME/CFS patient subgroups.
 

Wonkmonk

Senior Member
Messages
1,006
Location
Germany
Something that can be asserted without evidence can also be dismissed without evidence.
I wouldn't go so far. You could shut down every speculative line of scientific inquiry with this argument (including the autoimmunity hypothesis).
If I were a philanthropist and I had to place a bet, but could only fund one research stream in ME/CFS, I would put my money on the abortive herpes virus theory.
 

Sidny

Senior Member
Messages
176
I wouldn't go so far. You could shut down every speculative line of scientific inquiry with this argument (including the autoimmunity hypothesis).
If I were a philanthropist and I had to place a bet, but could only fund one research stream in ME/CFS, I would put my money on the abortive herpes virus theory.


Agreed. Also you wouldn't find viremia necessarily especially considering some of these herpes viruses are by their very nature, neurotropic. They live in the nerves not blood- the symptoms can be explained by a perpetual attack on those nerves (in which the virus lives). So it's not even autoimmunity really, the immune system is attacking a pathogen in tissue it basically has no chance of clearing. The vagus nerve infection theory I think explains this idea well.
 
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Sidny

Senior Member
Messages
176
I totally get this, but we have to remember that most people who get EBV and other herpesviruses do not have immune dysfunction or neuropathy, at least after the acute phase of the infection. We have coevolved with these viruses for a long time and although they have shaped and certainly play a role in the peculiarities of our immune systems, there must be some further underlying issue that causes some of us to get chronic illnesses. In my opinion anyway. Many of us, myself included, have had isolated periods, perhaps hours or days, perhaps longer, of remission or near-remission since becoming ill. I would be interested to know what changes during these periods. I would bet it's got nothing to do with low-level viral populations or antibody titers to viruses. And furthermore, I would imagine there is some way to replicate these conditions and dramatically improve symptoms if we can understand the molecular basis for all these different conditions more generally.


In my case I had a very traumatic onset and have not had any period of relief at all since it started. I had a uti and oral infection I believe was a primary hsv infection. Then I was given several courses of antibiotics which I believe destroyed or severely hindered many aspects of my immunity further compromising my bodies ability to keep these viruses at bay. Thus resulting in dissemination of the virus into tissues they would otherwise not have had a chance to reach. Being highly stressed with likely exaggerated cortisol levels for weeks on end likely contributed to the severity of my illness.

Upon finally catching a breath a month after my initial infection I went for a walk in the hills and with practically no good bacteria left I got wacked by a couple of ticks. If I did indeed contract Lyme which apparently is immunosuppressive and neurotropic.. well, then I guess quite a few of these exposures could have confounded and resulted in my current state of health. Kind of along the lines of the successive infection or "snow ball" effect.

But you're right it would be interesting to find out what's going on during periods of remission for people who experience it and figure out a way to sustain it. I think this disease is on a spectrum as no two peoples immunities or exposures are exactly the same. One thing I think we all have in common though are pretty bad cases of autonomic dysfunction indicated by cns invovmemnt although we didn't all arrive there in the same manner
 

Wonkmonk

Senior Member
Messages
1,006
Location
Germany
Agreed. Also you wouldn't find viremia necessarily especially considering some of these herpes viruses are by their very nature, neurotropic. They live in the nerves not blood- the symptoms can be explained by a perpetual attack on those nerves (in which the virus lives). So it's not even autoimmunity really, the immune system is attacking a pathogen in tissue it basically has no chance of clearing. The vagus nerve infection theory I think explains this idea well.

I think Dr Lerner's theory is that the herpes virus latently infects cells without the immune system noticing.

Usually, once it gets reactivated (e.g. HSV-1 by heat stress during fever), the reactivated cells start producing new virions and once these virions have been produced, destroys the cell deliberately so they can go into the blood stream. The virus usually does this when the body is already weakened (e.g. during a different infection). Under these circumstances it can overwhelm the immune system and cause temporary viremia or an outbreak like Shingles or a cold sore and thus infect other hosts. At the same time, it enters and latently infects other cells within the host, so it is never cleared.

If I understand Dr Lerner's theory correctly, he thinks that in CFS - possibly after a reactivation trigger like an infection - the virus for some reason latently infects cells and in these cells produces new 'half-baked' virions that are not complete. For some reason, the virus is also not destroying the cell, but at some point the cell understands it is latently infected and goes into apoptosis, which releases the half-complete viral particles into the blood where they can latently infect other cells and do the same thing.

Because no complete virions are formed, you never see a cold sore and you never see viremia via PCR, but what you do see is Viral Capsid Antigen antibodies because the unfinished virions already have these antigens.

Symptoms are explained because cells get destroyed via apoptosis, are dysfunctional while the virus tries to multiply and because there is a permanent low-level immune reaction against the released viral particles.
 

Sidny

Senior Member
Messages
176
@Wonkmonk
Thanks for the well articulated and detailed explanation of the abortive virus theory. It makes a lot of sense. Also, another factor may be the type of hsv strain- dozens have been identified apparently, some more virulent than others and are known to recombine so that may further explain beside the hosts immune response or coinfections, why some infections cause more trouble than others.
 
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used_to_race

Senior Member
Messages
193
Location
Southern California
Because no complete virions are formed, you never see a cold sore and you never see viremia via PCR, but what you do see is Viral Capsid Antigen antibodies because the unfinished virions already have these anti
I think Dr Lerner's theory is that the herpes virus latently infects cells without the immune system noticing.

Usually, once it gets reactivated (e.g. HSV-1 by heat stress during fever), the reactivated cells start producing new virions and once these virions have been produced, destroys the cell deliberately so they can go into the blood stream. The virus usually does this when the body is already weakened (e.g. during a different infection). Under these circumstances it can overwhelm the immune system and cause temporary viremia or an outbreak like Shingles or a cold sore and thus infect other hosts. At the same time, it enters and latently infects other cells within the host, so it is never cleared.

If I understand Dr Lerner's theory correctly, he thinks that in CFS - possibly after a reactivation trigger like an infection - the virus for some reason latently infects cells and in these cells produces new 'half-baked' virions that are not complete. For some reason, the virus is also not destroying the cell, but at some point the cell understands it is latently infected and goes into apoptosis, which releases the half-complete viral particles into the blood where they can latently infect other cells and do the same thing.

Because no complete virions are formed, you never see a cold sore and you never see viremia via PCR, but what you do see is Viral Capsid Antigen antibodies because the unfinished virions already have these antigens.

Symptoms are explained because cells get destroyed via apoptosis, are dysfunctional while the virus tries to multiply and because there is a permanent low-level immune reaction against the released viral particles.

My problem with this hypothesis is that it seems very difficult to validate and it doesn't really seem to be a simple explanation. It raises more questions than it answers. Why are our immune systems incapable of completely controlling the virus when others' immune systems can? What do these "half-baked" virions look like and how would scientists go about developing PCR assays that can identify them?

I would love to know whether any ongoing research is going to be able to shed some light on this. And if none of the current research focuses on this then I would like to know why the researchers decided to go in a different direction. Most of us here on the forums do not have the background in virology and immunology to evaluate these claims. True, there is a lot of noise in the MS and Alzheimer's research communities regarding the possible long-term effects of EBV but there has been very little actual evidence as far as I know.

This isn't really a thread about chronic viral infections but it helps illustrate a broader point: people with idiopathic dry eye syndrome have an increased risk for CFS, but that doesn't mean there is a causal relationship at play. Maybe both things are endpoints of the same root cause. Likewise, maybe CFS and high EBV or HSV titers could be unrelated endpoints of the same root cause.
 

Wonkmonk

Senior Member
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Germany
What do these "half-baked" virions look like and how would scientists go about developing PCR assays that can identify them?

That's what I am struggling with the most, too. Why didn't Dr Lerner find the unfinished viral particles? If they are there, would that be so hard to do given that it is a virus whose structure, antigens, RNA etc. is well known? We'd actually know what we would be looking for. It's not like searching for a completely new virus (and even that was detected quickly, e.g. in the case of HIV).

Then there are the EBV EA antibodies, that might help provide at least some evidence for the theory, but they are not there in every patient that responded to his treatment.

If herpes virus can be responsible for dry eyes, It would be interesting to go back to those of Dr Lerner's who did respond to antiherpetic treatment and ask them if they had dry eyes, too. It might be another stone in the mosaic.
 

Wishful

Senior Member
Messages
5,684
Location
Alberta
One question that should be asked for any of these hypotheses for the cause of ME/CFS is: does it fit with temporary full remissions that can occur over the space of minutes, lasting for hours? I don't understand the immune system well enough to rule that out for this hypothesis, but it seems that viral-caused changes would likely take place over a longer time frame. The leaky gut syndrome as a cause hypothesis also seems to fail this test. To me, a more likely hypothesis involves a feedback look involving cytokines or mitochondrial function (maybe both).
 

Sidny

Senior Member
Messages
176
If herpes virus can be responsible for dry eyes, It would be interesting to go back to those of Dr Lerner's who did respond to antiherpetic treatment and ask them if they had dry eyes, too. It might be another stone in the mosaic.

This would be of great interest to me. HSV is one of the leading causes of infectious blindness in the United States so there's no disputing its effects on the eyes. Hopefully the human herpes viruses will be taken more seriously and better treatments become available, in the way of cures or at least a vaccine.
 

Wonkmonk

Senior Member
Messages
1,006
Location
Germany
I am playing with the thought of trying miltefosine. It has been shown to block HSV-1 viral entry into the cell (by inhibiting Akt):

https://www.sciencedirect.com/science/article/pii/S0042682215000860

If Dr Lerner's theory is correct, current antiherpetic medications (nucleoside analogues) cannot effectively stop abortive infection because they stop viral replication at a late state in the cycle. There are no known drugs that stop the formation of early viral gene products (Dr Lerner explicitly states that in one of his studies).

Blocking viral entry would be the earliest stage one could possibly try to stop, so this might help prevent the virus from spreading (assuming the half-baked virions also need Akt to enter the cell).

What I find so interesting is that Akt is tied to the cells calcium metabolism and leads to influx of calcium into the cell. The virus seems to need higher calcium concentrations to enter the cells.

This is intriguing because I have on several occasions become reliably much worse when I use Vitamin D or calcium supplements and also sunlight exposure. It also in each case coincided with a new type of are of my body to be affected - in one case my eyes started to get red and dry (!), in the second my hip joint began to ache and in the third I got back pain.

All these symptoms appeared for the first time after I used both calcium and vitamin D in higher doses and all appeared in the summer when vitamin D is higher due to sunshine.

Calcium makes me reliably worse and leads to new symptoms in new parts of the body and I read the same thing for a couple of reports here that say the same. Herpes simplex needs calcium to enter the cells. Coincidence? I don't think so.
 

pibee

Senior Member
Messages
304
maybe many are seronegative Sjogren's patients. I wonder are early Sjo antibodies checked in ME/CFS cohorts. @Janet Dafoe (Rose49)

http://www.bausch.com/ecp/our-products/diagnostics/sjo

I have confirmed Sjogren's now, I am not sure it excludes ME though as many of my symptoms (PENE/PEM) are ME.
So far I know I have Sjogrens, POTS (very autoimmune too) and Hashimoto. My CNS problems remain a mistery, as they shouldnt be a complication of Sjogren's since I dont have MRI lesions.
 
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Belbyr

Senior Member
Messages
602
Location
Memphis
maybe many are seronegative Sjogren's patients. I wonder are early Sjo antibodies checked in ME/CFS cohorts. @Janet Dafoe (Rose49)

http://www.bausch.com/ecp/our-products/diagnostics/sjo

I have confirmed Sjogren's now, I am not sure it excludes ME though as many of my symptoms (PENE/PEM) are ME.
So far I know I have Sjogrens, POTS (very autoimmune too) and Hashimoto. My CNS problems remain a mistery, as they shouldnt be a complication of Sjogren's since I dont have MRI lesions.

I would suggest if anyone has questions as to whether their nervous system has damage or if you have sjogrens... I strongly suggest Dr Chemali in Norfolk. He is the best and most thorough neurologist I have been to! Nurses are quite amazing as well.
 

percyval577

nucleus caudatus et al
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Ik waak up
Maybe just the opposite: I had for years my one eye constantly wet when riding bike.
(Obviously it has stopped two years ago after reducing manganese intake since three years.)
 

StarChild56

Senior Member
Messages
1,405
This actually can be a sign of dry eyes.

Yes, while my eyes felt gritty and sore, sometimes they leak when I am laying down especially on my side so I never thought of "dry eyes". My Ophthalmologist explained why, which I don't remember but I have dry eyes dxd by Schirmer's test. And SS.