Hmm, I didn't realise that Lyme can cause endothelial dysfunction:
http://www.researchgate.net/publica...nction_Markers_with_the_Course_of_Borreliosis
http://www.researchgate.net/publica...nction_Markers_with_the_Course_of_Borreliosis
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Endothelial dysfunction in Lyme
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anciendaze
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What we may be seeing is a correlation between immune dysfunction and chronic infectious diseases causing diffuse inflammation. This looks like a preclinical manifestation of a wide range of pathologies. You might check for endothelial dysfunction in relation to stroke, hypertension, cardiovascular disease or kidney disease.
anciendaze
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I'm suggesting we might be seeing evidence of immune dysfunction preceding a wide range of pathologies. This would not imply specific causation by any particular pathogen.
anciendaze
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I'm suggesting Lyme and a range of other infections become more serious problems only when immune response has a subtle defect current understanding of immune function does not recognize. That is, causation from immune dysfunction is the key in many pathologies, of which borreliosis is only one.
People working from correlations frequently make mistakes comparable to concluding that ice cream sales on Coney Island cause cholera in India, though less obvious. The correlation is the result of a common factor contributing to both, summer in the northern hemisphere.
People working from correlations frequently make mistakes comparable to concluding that ice cream sales on Coney Island cause cholera in India, though less obvious. The correlation is the result of a common factor contributing to both, summer in the northern hemisphere.
I do not think that is what the evidence suggests - Lyme seems well capable of causing the immune dysfunction itself. Why do more post-menopausal women get chronic Lyme more frequently than men? It seems to have something to do with a th-2 shift around this time. Does that mean that post-menopausal women are immune-deficient?
anciendaze
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Not by current standards, but I think a narrow specific vulnerability may become worse at this time. This happens with a great many other medical problems. Our problem is that we have no way to assess immune competence, only immune incompetence. Right up to the point where we lose the ability to hold infections latent current tests say everything is good.
I will agree that borreliosis makes immune problems worse, sometimes much worse. A long list of infectious diseases also make people more vulnerable to other infections. Immune response works best when it is a matter of a healthy body concentrating on a single clearly-identified pathogen. The ability of pathogens like borrelia to mask themselves has many other implications.
I agree with what you said, but I think there is a danger of it becoming a truism - i.e people who have Lyme have immune systems that are not good at getting rid of Lyme. The important question here, is where to intervene - should we screen everyone for th2 shifts, for example, or should we screen people with ME more effectively for Lyme, and other pathogens that can cause a similar condition (such as Q fever) I think the second approach is much more practical, and it also has the advantage that we have more effective ways of treating Lyme and Q fever than we do of changing the immune system.
anciendaze
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@msf
I am not impressed with current screening technologies. I think the fact that tests for Lyme have been approved when they have high rates of false negatives should be a scandal. They look to me like solutions to political problems rather than medical ones.
To really rule out Lyme with current tests you would need about three negative tests. The chances of getting a false positive then become too high to ignore. You might also have a species of borrelia not currently considered a serious threat, like b. miyamotoi. This still leaves out such possible bacterial infections as bartonellosis or erlichiosis or other anaplasmoses or rickettsias, let alone parasites like babesia.
If you should happen to go to a doctor and say "doc, I think I'm infected with babesia microti" current tests are mostly useful for validating the standard response "Nah, you don't have any such thing." Diagnostic thresholds for clinical signs and immune response have been set high so doctors can ignore ambiguous cases where the possibility of misdiagnosis and malpractice are high. The thinking seems to be that people with real diseases will present with convenient signs. If you don't catch it early someone will catch it later, possibly at autopsy.
We need some way to tell what immune systems are doing which does not depend on correct functioning of the same system, the way tests for antibodies do.
I am not impressed with current screening technologies. I think the fact that tests for Lyme have been approved when they have high rates of false negatives should be a scandal. They look to me like solutions to political problems rather than medical ones.
To really rule out Lyme with current tests you would need about three negative tests. The chances of getting a false positive then become too high to ignore. You might also have a species of borrelia not currently considered a serious threat, like b. miyamotoi. This still leaves out such possible bacterial infections as bartonellosis or erlichiosis or other anaplasmoses or rickettsias, let alone parasites like babesia.
If you should happen to go to a doctor and say "doc, I think I'm infected with babesia microti" current tests are mostly useful for validating the standard response "Nah, you don't have any such thing." Diagnostic thresholds for clinical signs and immune response have been set high so doctors can ignore ambiguous cases where the possibility of misdiagnosis and malpractice are high. The thinking seems to be that people with real diseases will present with convenient signs. If you don't catch it early someone will catch it later, possibly at autopsy.
We need some way to tell what immune systems are doing which does not depend on correct functioning of the same system, the way tests for antibodies do.
I agree, but any improvement on the current two-tier test would help, and there are several options available: get rid of the ELISA portion, use a C6 peptide test, or use the LTT tests.
The problem with a lot of doctors is that they do not educate themselves about new developments in fields such as Lyme, and just do whatever their guidelines (which were written decades ago, when little was known about these conditions) say. Then, when you confront them on this, they just obfuscate until you give up and go away. At least, that has been my experience with the NHS.
The problem with a lot of doctors is that they do not educate themselves about new developments in fields such as Lyme, and just do whatever their guidelines (which were written decades ago, when little was known about these conditions) say. Then, when you confront them on this, they just obfuscate until you give up and go away. At least, that has been my experience with the NHS.
anciendaze
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The way such a situation came about could be a study in historical contingency. Borrelia burgdorferi did not suddenly spring into existence in the 1970s. The "Iceman" found in an alpine glacier tested positive for some species of borrelia. I am less concerned about how such mistakes are made than I am with why they remain screwed up. We are now about half a century away from recognition of a distinct disease, and the unsatisfactory situation remains.
In this country, when the federal government is not hostile to questions about Lyme disease, they are largely indifferent. This may well be because Lyme treatment is not something they will pay for, beyond 6 weeks of oral doxycycline when a patient in the right geographic area presents with a bullseye rash. (I am in the wrong area, even if I had such a rash.)
The result of this kind of laissez faire of private practice is that I would have no trouble finding a local doctor who would diagnose me with Lyme, based on possibly unreliable tests, then treat me with months of IV antibiotics. I would also have no trouble finding doctors who would tell me I couldn't possibly have Lyme. There are doctors I would describe as heros, and there are doctors engaged in shearing ignorant sheep. Large numbers are simply like postal workers, merely going through the motions without worrying too much about possible content of their deliveries.
Why is this tolerated?
In this country, when the federal government is not hostile to questions about Lyme disease, they are largely indifferent. This may well be because Lyme treatment is not something they will pay for, beyond 6 weeks of oral doxycycline when a patient in the right geographic area presents with a bullseye rash. (I am in the wrong area, even if I had such a rash.)
The result of this kind of laissez faire of private practice is that I would have no trouble finding a local doctor who would diagnose me with Lyme, based on possibly unreliable tests, then treat me with months of IV antibiotics. I would also have no trouble finding doctors who would tell me I couldn't possibly have Lyme. There are doctors I would describe as heros, and there are doctors engaged in shearing ignorant sheep. Large numbers are simply like postal workers, merely going through the motions without worrying too much about possible content of their deliveries.
Why is this tolerated?
anciendaze
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Just using this as a convenient place to post links to material on endothelial dysfunction, with or without Lyme disease. There has long been awareness that endothelial dysfunction not only precedes cardiovascular disease, but has actual predictive value for dangerous events. See this paper. Another consequence of endothelial dysfunction shows up in renal disease. It also figures large in complications of diabetes. None of these consequences could be called trivial.
One problem with the hypothesis that oxydative stress is the villain here is that treatment with common antioxidants shows no particular improvement. What I noted some time ago was that a major pathway for disposing of misfolded proteins uses ATP molecules. These are attached to proteins to mark them for disposal, and also serve to power the cellular machinery doing the job. Production of reactive oxygen species seems to play a positive role in response to pathological conditions involving those misfolded proteins.
This definitely uses up cellular energy which might otherwise be available for muscle activity, and that is part of the malaise we commonly associate with infectious illness.
At this point we don't know if this is the real problem or a response to another problem we have not identified, like occult infection. We do know that patients bodies are behaving as if they are under attack by pathogens even if those pathogens are hard to identify or isolate. It is possible the cellular machinery which identifies and degrades these molecules is defective. It is possible it is simply overloaded. Until we know why this process is so active we must be very careful that we do not exacerbate undetected problems by interfering with response to a real undetected condition.
One problem with the hypothesis that oxydative stress is the villain here is that treatment with common antioxidants shows no particular improvement. What I noted some time ago was that a major pathway for disposing of misfolded proteins uses ATP molecules. These are attached to proteins to mark them for disposal, and also serve to power the cellular machinery doing the job. Production of reactive oxygen species seems to play a positive role in response to pathological conditions involving those misfolded proteins.
This definitely uses up cellular energy which might otherwise be available for muscle activity, and that is part of the malaise we commonly associate with infectious illness.
At this point we don't know if this is the real problem or a response to another problem we have not identified, like occult infection. We do know that patients bodies are behaving as if they are under attack by pathogens even if those pathogens are hard to identify or isolate. It is possible the cellular machinery which identifies and degrades these molecules is defective. It is possible it is simply overloaded. Until we know why this process is so active we must be very careful that we do not exacerbate undetected problems by interfering with response to a real undetected condition.
Great discussion! Good topic that in some ways acts as a microcosm of the persistent pathogen vs immune dysfunction debate, and easily reflects the multi-tiered aspects swirling about it. It's simply not an easy nut.
I swear my opinion changes too often, and I find little solace in Emmerson's admonitions about worrying too much over inconsistencies.
And obviously one condition does not preclude the absence of the other, either.
The thing that inclines me to persistent Borrelia is the misrepresentations that mainstream Lyme seems liberally to indulge in, imo. But that is arguably irrelevant.
I hope I haven't misinterptreted or oversimplified either the opinions of @msf or @anciendaze , although I suspect I have.
I swear my opinion changes too often, and I find little solace in Emmerson's admonitions about worrying too much over inconsistencies.
And obviously one condition does not preclude the absence of the other, either.
The thing that inclines me to persistent Borrelia is the misrepresentations that mainstream Lyme seems liberally to indulge in, imo. But that is arguably irrelevant.
I hope I haven't misinterptreted or oversimplified either the opinions of @msf or @anciendaze , although I suspect I have.
anciendaze
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@duncan
Elsewhere, I've stated a couple of other aspects of the debate which don't fit usual dichotomies. One is that a persistent pathogen is an immune dysfunction. Healthy immune systems are remarkably good at either destroying pathogens, or forcing them to remain inactive. We now know things that Koch did not know about such standbys as mycobacterium tuberculosis. Most infected people do not show classic clinical signs of TB. Even up to 99% of those who ultimately develop the full disease do not move directly to acute disease. There is a long period when most patient immune systems control it. Just a slight improvement in very specific immune activity here would make them effectively immune to the disease. In this regard the BCG vaccine, while useful, has proved a disappointment. Why don't we have a TB vaccine with high effectiveness?
Another modern problem comes from the Balkanization of medicine into specializations. Before a patient reaches a specialist dealing with Lyme or ME/CFS she/he is likely to have consulted several doctors. If any of those recognize a serious problem connected with a single organ system, like the heart, pancreas or kidneys mentioned above, the patient will be shunted into a different therapeutic track, and the doctors for less-specific diseases will never see them. It doesn't matter that many recognized conditions are "of unknown etiology", most specialists aren't concerned about anything except severe disease meeting their diagnostic standards. Part of the reason is that available interventions may be as drastic and risky as a heart bypass.
The result is that statistics associated with neglected diseases suffer from serious sampling errors because various doctors in high-prestige specializations like cardiology "know" the problems they treat have nothing to do with less serious preclinical conditions. Not only do patients who somehow avoid going down the path to immediately dangerous pathology suffer neglect, those patients who do were not given any useful advice which might have prevented disease except exhortations to eat healthy, exercise and avoid X, Y or Z.
After some effort in searching literature on the effects of exercise I have concluded that nobody had carefully tested to see if causation was always from exercise => health instead heath => exercise. If they had, the discovery that a few patients have reduced capacity lasting long after exercise would not have been a surprise.
I have also noted that people who have great trouble "eating healthy" usually pick foods with high energy content to splurge on. In one case, the patient was not able to control weight despite really drastic measures. Last I heard, her pituitary was almost completely calcified. This not only raises questions about incidence of pituitary damage for unknown reasons, it also makes me wonder how much of "healthy eating" is a lack of craving for unhealthy foods caused by metabolic defects. Had diabetes been labeled "chronic thirst disease", and considered subjective, I doubt research on it would have gotten very far.
Elsewhere, I've stated a couple of other aspects of the debate which don't fit usual dichotomies. One is that a persistent pathogen is an immune dysfunction. Healthy immune systems are remarkably good at either destroying pathogens, or forcing them to remain inactive. We now know things that Koch did not know about such standbys as mycobacterium tuberculosis. Most infected people do not show classic clinical signs of TB. Even up to 99% of those who ultimately develop the full disease do not move directly to acute disease. There is a long period when most patient immune systems control it. Just a slight improvement in very specific immune activity here would make them effectively immune to the disease. In this regard the BCG vaccine, while useful, has proved a disappointment. Why don't we have a TB vaccine with high effectiveness?
Another modern problem comes from the Balkanization of medicine into specializations. Before a patient reaches a specialist dealing with Lyme or ME/CFS she/he is likely to have consulted several doctors. If any of those recognize a serious problem connected with a single organ system, like the heart, pancreas or kidneys mentioned above, the patient will be shunted into a different therapeutic track, and the doctors for less-specific diseases will never see them. It doesn't matter that many recognized conditions are "of unknown etiology", most specialists aren't concerned about anything except severe disease meeting their diagnostic standards. Part of the reason is that available interventions may be as drastic and risky as a heart bypass.
The result is that statistics associated with neglected diseases suffer from serious sampling errors because various doctors in high-prestige specializations like cardiology "know" the problems they treat have nothing to do with less serious preclinical conditions. Not only do patients who somehow avoid going down the path to immediately dangerous pathology suffer neglect, those patients who do were not given any useful advice which might have prevented disease except exhortations to eat healthy, exercise and avoid X, Y or Z.
After some effort in searching literature on the effects of exercise I have concluded that nobody had carefully tested to see if causation was always from exercise => health instead heath => exercise. If they had, the discovery that a few patients have reduced capacity lasting long after exercise would not have been a surprise.
I have also noted that people who have great trouble "eating healthy" usually pick foods with high energy content to splurge on. In one case, the patient was not able to control weight despite really drastic measures. Last I heard, her pituitary was almost completely calcified. This not only raises questions about incidence of pituitary damage for unknown reasons, it also makes me wonder how much of "healthy eating" is a lack of craving for unhealthy foods caused by metabolic defects. Had diabetes been labeled "chronic thirst disease", and considered subjective, I doubt research on it would have gotten very far.
No, you didn't misrepresent my opinion. I guess I feel I understand infectious disease more than I understand immune dysfunction, and I also prefer simple explanations, so I gravitate towards the persistent pathogen argument. I guess we will just have to wait to find out who is right, or it could be that both camps are right - i.e, that there is an underlying immune dysfunction that allows a pathogen such as Lyme to trigger ME.
Anciendaze, I think the argument that a persistent infection shows that someone has a dysfunctional pathogen depends on the pathogen you are talking about, and your definition of immune dysfunction. So for things like Mycoplasma (I forget which one the paper I read was referring to) something like 10% of people go on to be chronically infected. This is likely to be partly a result of genetics. So you could define this as a specific immune dysfunction. Something similar is likely to be the case with Yersinia Pseudotuberculosis, as the one epidemiological study that has been done showed that about 8% of those went on to develop Reactive Arthritis (I believe there is sufficient evidence to show that this is caused by persistence of the causative pathogen). But it seems possible, indeed quite likely, to me that almost everyone will have some specific immune dysfunction.
You also have pathogens like HIV, which causes persistent and symptomatic infection in most, if not all, of those infected. I think it would be meaningless to talk about immune dysfunction in this case.
I think it is likely that Lyme is somewhere in the middle of this spectrum. So it might make sense to talk about a specific immune dysfunction, or even a general one, like a th2-shift, but I still think the best, and simplest, way to start looking into these possibilities is to try to determine the prevalence of Lyme (and other pathogens that can result in an ME-like disease) in ME patients, using the most sensitive tests available.
You also have pathogens like HIV, which causes persistent and symptomatic infection in most, if not all, of those infected. I think it would be meaningless to talk about immune dysfunction in this case.
I think it is likely that Lyme is somewhere in the middle of this spectrum. So it might make sense to talk about a specific immune dysfunction, or even a general one, like a th2-shift, but I still think the best, and simplest, way to start looking into these possibilities is to try to determine the prevalence of Lyme (and other pathogens that can result in an ME-like disease) in ME patients, using the most sensitive tests available.
anciendaze
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@msf
I'm saying that whether or not a person with a persistent infection had an inherited immune defect, they will definitely have an immune defect while the infection persists. Successful human pathogens have to evade or misdirect immune response to persist without becoming completely inactive.
I'm not sure what point you are making about HIV-1. The mean latency from infection to symptoms is typically 5 years, and most appear healthy during this period in the absence of specific tests. One of the problems in control is that a victim can pass it to a lot of others before the disease makes itself apparent or impairs the carrier.
In the case of HTLV-1, latency regularly exceeds 20 years, even in those who ultimately develop neurodegenerative disease or neoplasms. This makes me wonder how much normal aging and mortality is due to similar causes which have been ignored because "everyone has them".
Here we get into a problem with the way infectious diseases are defined as a medical specialization. If the pathogen replicates rapidly, and numbers grow exponentially, it will be easy to detect at some stage, possibly autopsy. This basically limits those specialists to treating progressive diseases, not chronic. Even something like Legionnaires' disease took a great effort to explain, after a conspicuous series of deaths had occurred. This also struck down people old enough to have some degree of immunosenscence.
What I'm trying to do is come at the problem from a different direction from disputes which remind me of my days on a playground where participants said "is"/"isn't". If we can figure out how b. burgdorferi distorts immune response to protect itself we should have a better test for that infection. For the larger problem of all possible pathogens producing long-term "flu-like" symptoms, we will need even better understanding. Doing the same thing we are doing now, only more so does not look like a good answer.
You can literally spend thousands of dollars searching for such individual causes with current technology, and still end up with a "maybe" answer. If you try treating all potential infections you will be lucky to escape with your life, and your bank account will take a large hit.
I'm saying that whether or not a person with a persistent infection had an inherited immune defect, they will definitely have an immune defect while the infection persists. Successful human pathogens have to evade or misdirect immune response to persist without becoming completely inactive.
I'm not sure what point you are making about HIV-1. The mean latency from infection to symptoms is typically 5 years, and most appear healthy during this period in the absence of specific tests. One of the problems in control is that a victim can pass it to a lot of others before the disease makes itself apparent or impairs the carrier.
In the case of HTLV-1, latency regularly exceeds 20 years, even in those who ultimately develop neurodegenerative disease or neoplasms. This makes me wonder how much normal aging and mortality is due to similar causes which have been ignored because "everyone has them".
Here we get into a problem with the way infectious diseases are defined as a medical specialization. If the pathogen replicates rapidly, and numbers grow exponentially, it will be easy to detect at some stage, possibly autopsy. This basically limits those specialists to treating progressive diseases, not chronic. Even something like Legionnaires' disease took a great effort to explain, after a conspicuous series of deaths had occurred. This also struck down people old enough to have some degree of immunosenscence.
What I'm trying to do is come at the problem from a different direction from disputes which remind me of my days on a playground where participants said "is"/"isn't". If we can figure out how b. burgdorferi distorts immune response to protect itself we should have a better test for that infection. For the larger problem of all possible pathogens producing long-term "flu-like" symptoms, we will need even better understanding. Doing the same thing we are doing now, only more so does not look like a good answer.
You can literally spend thousands of dollars searching for such individual causes with current technology, and still end up with a "maybe" answer. If you try treating all potential infections you will be lucky to escape with your life, and your bank account will take a large hit.
anciendaze
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I had to break for dinner while writing the last post, so I did not have time to make it shorter (to quote Mark Twain.) This post will compound the problem.
We have been marginalized in a number of ways, but one of them is that every connection with serious diseases has been denied, and patients who develop those diseases end up in the hands of different doctors. This even extends to the point of removing patients who develop lymphomas from cohorts on the grounds that they never had ME/CFS, even though there was no diagnostic test which could distinguish them. This is carried to such an extent that you can't even get any official figures for ME/CFS patients who develop heart disease, cancer, autoimmune disease, diabetes, liver disease, stroke, renal disease, etc. This is for a group said to consist of over 2 million U.S. citizens. Would we be better studied if we were Eskimos?
In the case of Lyme disease we have a slightly different form of disparagement. Official material will say, for example, that Lyme disease can cause fatal heart problems, because there have been 5 documented cases in 40 years. (Only 5? What does this tell your PCP?) Figures for neuroborreliosis are even less clear, as it can cause, e.g. seizures, but officials are certain it is not a factor in the rising incidence of dementia. (Why?)
Connecting these diseases with preclinical causes of acknowledged life-threatening conditions should stop the tactic of pitting us against entrenched pressure groups demanding funds for research on pathologies that may be too far advanced to cure at present by the time clear diagnosis can be made. I am not advocating abandoning patients with heart failure, diabetes, dementia or renal failure. I am simply pointing out that unless steps are taken earlier to prevent these conditions from developing the funds necessary to care for those who have them will not cover the increasing number of cases now projected.
Above, I've linked papers describing endothelial dysfunction as a precursor of several conditions with significant mortality and morbidity. I can supply more. If prevention of these conditions is not worth more funding than male-pattern baldness we might as well give up on the idea of government-funded medical research as anything except a classier form of pork barrel politics.
We have been marginalized in a number of ways, but one of them is that every connection with serious diseases has been denied, and patients who develop those diseases end up in the hands of different doctors. This even extends to the point of removing patients who develop lymphomas from cohorts on the grounds that they never had ME/CFS, even though there was no diagnostic test which could distinguish them. This is carried to such an extent that you can't even get any official figures for ME/CFS patients who develop heart disease, cancer, autoimmune disease, diabetes, liver disease, stroke, renal disease, etc. This is for a group said to consist of over 2 million U.S. citizens. Would we be better studied if we were Eskimos?
In the case of Lyme disease we have a slightly different form of disparagement. Official material will say, for example, that Lyme disease can cause fatal heart problems, because there have been 5 documented cases in 40 years. (Only 5? What does this tell your PCP?) Figures for neuroborreliosis are even less clear, as it can cause, e.g. seizures, but officials are certain it is not a factor in the rising incidence of dementia. (Why?)
Connecting these diseases with preclinical causes of acknowledged life-threatening conditions should stop the tactic of pitting us against entrenched pressure groups demanding funds for research on pathologies that may be too far advanced to cure at present by the time clear diagnosis can be made. I am not advocating abandoning patients with heart failure, diabetes, dementia or renal failure. I am simply pointing out that unless steps are taken earlier to prevent these conditions from developing the funds necessary to care for those who have them will not cover the increasing number of cases now projected.
Above, I've linked papers describing endothelial dysfunction as a precursor of several conditions with significant mortality and morbidity. I can supply more. If prevention of these conditions is not worth more funding than male-pattern baldness we might as well give up on the idea of government-funded medical research as anything except a classier form of pork barrel politics.
lansbergen
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