I’m having discussions with some people who say it is possible to have viral reactivation of viruses, especially herpes family viruses like EBV, even if you have PCR tests that show no detectable viral DNA. They believe that the viral reactivation is reflected by high levels of IgG and IgM antibodies to the virus. I’m more in the camp that believes that the high Ig levels might just be residual from the initial infection. Does anyone have any idea about this?
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Can you have “viral reactivation” if you have a negative PCR test for viral DNA?
- Thread starter Jaybee00
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Re-reading JE’s post in this thread https://www.s4me.info/threads/epstein-barr-virus-ebv-testing-pcr-versus-serology.44896/
it seems like it is possible to just miss the virus reactivation event if you aren’t doing the PCR test like everyday. I wonder if there is an actual reactivation event, for how many days will the PCR test detect virus DNA? A day, a week, a month?
it seems like it is possible to just miss the virus reactivation event if you aren’t doing the PCR test like everyday. I wonder if there is an actual reactivation event, for how many days will the PCR test detect virus DNA? A day, a week, a month?
Jonathan Edwards
Senior Member (Voting Rights)
It must be possible to have local replication of virus and miss it with blood PCR but it starts to become semantic whether this counts as a 'reactivation'.
In general I think the idea that serological levels of IgG or IgM can tell you there is reactivation when PCR is negative is just bad medicine likely promoted by fringe specialists. If there is a doubling in IgM and/or IgG levels in a specific window of time, like two weeks, that may be significant, but I would only take it seriously if the two samples had been deliberately taken as a pair and run on the same assay. Otherwise it might be a fluctuation in assay conditions.
I do not see any mileage in any of this. It is pretty much entirely driven by memes spread by private physicians who don't really understand immunology or virology. Some patients like it as an explanation but at best it is something that provides information about populations. Applicat5ion to individual people's illness is unlikely to be meaningful.
In general I think the idea that serological levels of IgG or IgM can tell you there is reactivation when PCR is negative is just bad medicine likely promoted by fringe specialists. If there is a doubling in IgM and/or IgG levels in a specific window of time, like two weeks, that may be significant, but I would only take it seriously if the two samples had been deliberately taken as a pair and run on the same assay. Otherwise it might be a fluctuation in assay conditions.
I do not see any mileage in any of this. It is pretty much entirely driven by memes spread by private physicians who don't really understand immunology or virology. Some patients like it as an explanation but at best it is something that provides information about populations. Applicat5ion to individual people's illness is unlikely to be meaningful.
wigglethemouse
Senior Member (Voting Rights)
Two studies come to mind.
1. Prusty found you can have viral proteins without replication that could cause an immune response. For HHV6A he studied U40 (a small non coding RNA I think) as a marker for latent reactivation. He then showed how that can affect model cells in the lab.
2. Jackie Cliff team found HHV6B in saliva with digital droplet PCR correlated with ME/CFS severity or was it disease state. So you might not find HHV6B PCR positive in blood, but it could be present in Saliva for example.
You would also have to take in clinical signs into the equation such as HSV1 sores.
1. Prusty found you can have viral proteins without replication that could cause an immune response. For HHV6A he studied U40 (a small non coding RNA I think) as a marker for latent reactivation. He then showed how that can affect model cells in the lab.
2. Jackie Cliff team found HHV6B in saliva with digital droplet PCR correlated with ME/CFS severity or was it disease state. So you might not find HHV6B PCR positive in blood, but it could be present in Saliva for example.
You would also have to take in clinical signs into the equation such as HSV1 sores.
jnmaciuch
Senior Member (Voting Rights)
There’s evidence in HIV that there is local low-level viral reactivation in the tissue where anti-virals don’t reach very well (it’s well documented in the brain, and is correlated with neurological symptoms) even when viral DNA is undetectable in the blood.
Though in the case of HIV-associated neurological disease, you do also have pretty clear signs of an immune response detectible in cerebrospinal fluid.
EBV is known to harbor in epithelial cells in the latency so it wouldn’t surprise me if it was possible to get transient viremia in these tissues. Especially since other infections and even various metabolic changes can knock EBV out of latency.
But it would probably have to stay at low levels locally to not be detectable in the blood, and this state is usually called viremia rather than re activation—a semantic distinction like @Jonathan Edwards notes. And I agree that Ig would be an unreliable marker except under very specific circumstances
Though in the case of HIV-associated neurological disease, you do also have pretty clear signs of an immune response detectible in cerebrospinal fluid.
EBV is known to harbor in epithelial cells in the latency so it wouldn’t surprise me if it was possible to get transient viremia in these tissues. Especially since other infections and even various metabolic changes can knock EBV out of latency.
But it would probably have to stay at low levels locally to not be detectable in the blood, and this state is usually called viremia rather than re activation—a semantic distinction like @Jonathan Edwards notes. And I agree that Ig would be an unreliable marker except under very specific circumstances
If you have these, then it's obvious something viral is going on no matter what the PCR tests say. There isn't much point in doing a fancy blood test if you have an obvious HSV sore. A clinical diagnosis is sufficient. And I've never heard an ME/CFS specialist say herpes sores have any significance for us. Otherwise healthy people can have cold sores when they get stressed, so not much specific info for us.
I think the issue is how we test for hidden viruses and when the clinical signs are ambiguous or nonspecific, like say fatigue. The question of whether or not long COVID people still have lingering virus, or even just viral particles doesn't seem to be pinned down yet, so it seems to me very unlikely if we'll get an answer about people who have had ME for longer years.
And even if we do have lingering viruses, I am very much in the dark about whether that matters. I mean most of us have had chicken pox when we were little... but what makes someone get shingles later on and someone else not?
boolybooly
Senior Member (Voting Rights)
How long is a piece of string? Duration of viral replication signal depends on the virus and the genetics of the immune system of the patient and their nutritional state and physical health.
Unknown whether there are masked modes, where an established immune response might hypothetically mop up reactivation signal before it can be detected.
As I understand it currently IgG is not regarded as signifying ongoing replication whereas IgM is regarded as signifying recent immune response to infection.
Only PCR is regarded as proof positive of active virus.
In the mid 1980s it was received wisdom in the NHS that viruses did not recur. I was told "that does not happen" referring to my report that HSV2 was recurring. This is patently untrue and received wisdom in GU medicine has since changed to accept herpes virus reactivation (while my own condition has subsequently been reconfirmed by multiple +ve PCR tests) proving lack of infallibility / omniscience on the part of the members of the medical profession. But that does not mean that every other medical conspiracy theory is true.
Preceding such fashionable fads and influences of political expedience on diagnosis, the medical consensus as evinced by some practitioners, accepted some people were more "delicate" than others and some illnesses especially EBV could reactivate for some people. I remember being warned about exactly that in the early 1980s after having EBV (confirmed by Paul Bunnell test) though what this really meant is anybody's guess. I was just told it was "really nasty" and told not to over do it. I wonder if such a description might have resulted from clinical observations of what we would now call ME, which at the time was considered post EBV relapse.
My more recent IgM assays do not indicate recent EBV activation though IgG confirms a prior infection, nevertheless there are occasional episodes when I feel the same characteristic EBV symptoms. There are people who will argue this is due to a memory effect but I know of no empirical evidence to support this theory. IMHO Occam's prefers the duck approach on a balance of probabilities, as a working hypothesis but of course one cannot claim certainty or provide medico-legal evidence on such a basis.
The association between EBV and subsequent health failure I was warned about makes me wonder whether EBV somehow set me up for other viruses to reactivate, because it is not just HSV2 which recurs symptomatically for me, theough it is the only one I can prove does.
If received medical wisdom was wrong once it can be wrong again. We dont fully understand the behaviour of viruses in vivo and we don't have testing systems which can regularly check for viral activity outside of the research context. One day we might but Theranos was a bust and the miniaturisation tech is not quite there yet but my hope is it will arrive in a decade or two, when we might all have 24/7 personalised medical testing of pee and poop and a daily pinprick of blood.
Until then we are mired in ignorance like the generations who came before us and suffered while they struggled their way out of the mud. We stand on their shoulders and while we owe them our gratitude, our duty to ourselves and the future is likewise to spend our today struggling for a better tomorrow. What else can we do?
Unknown whether there are masked modes, where an established immune response might hypothetically mop up reactivation signal before it can be detected.
As I understand it currently IgG is not regarded as signifying ongoing replication whereas IgM is regarded as signifying recent immune response to infection.
Only PCR is regarded as proof positive of active virus.
In the mid 1980s it was received wisdom in the NHS that viruses did not recur. I was told "that does not happen" referring to my report that HSV2 was recurring. This is patently untrue and received wisdom in GU medicine has since changed to accept herpes virus reactivation (while my own condition has subsequently been reconfirmed by multiple +ve PCR tests) proving lack of infallibility / omniscience on the part of the members of the medical profession. But that does not mean that every other medical conspiracy theory is true.
Preceding such fashionable fads and influences of political expedience on diagnosis, the medical consensus as evinced by some practitioners, accepted some people were more "delicate" than others and some illnesses especially EBV could reactivate for some people. I remember being warned about exactly that in the early 1980s after having EBV (confirmed by Paul Bunnell test) though what this really meant is anybody's guess. I was just told it was "really nasty" and told not to over do it. I wonder if such a description might have resulted from clinical observations of what we would now call ME, which at the time was considered post EBV relapse.
My more recent IgM assays do not indicate recent EBV activation though IgG confirms a prior infection, nevertheless there are occasional episodes when I feel the same characteristic EBV symptoms. There are people who will argue this is due to a memory effect but I know of no empirical evidence to support this theory. IMHO Occam's prefers the duck approach on a balance of probabilities, as a working hypothesis but of course one cannot claim certainty or provide medico-legal evidence on such a basis.
The association between EBV and subsequent health failure I was warned about makes me wonder whether EBV somehow set me up for other viruses to reactivate, because it is not just HSV2 which recurs symptomatically for me, theough it is the only one I can prove does.
If received medical wisdom was wrong once it can be wrong again. We dont fully understand the behaviour of viruses in vivo and we don't have testing systems which can regularly check for viral activity outside of the research context. One day we might but Theranos was a bust and the miniaturisation tech is not quite there yet but my hope is it will arrive in a decade or two, when we might all have 24/7 personalised medical testing of pee and poop and a daily pinprick of blood.
Until then we are mired in ignorance like the generations who came before us and suffered while they struggled their way out of the mud. We stand on their shoulders and while we owe them our gratitude, our duty to ourselves and the future is likewise to spend our today struggling for a better tomorrow. What else can we do?