HHV-6 Infection - IgG or IgM?

sometexan84

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Does anyone know for sure which one to test?

I'm using this article for reference - https://www.drmyhill.co.uk/wiki/Valacyclovir_in_the_treatment_of_post_viral_fatigue_syndrome

Quote from article:​
We then have to ask the question if there is any evidence of cytomegalovirus (CMV) or HHV-6 infection, which would require additional treatment with Valganciclovir. From his paper it does not appear that these two viruses are candidates for non-permissive replication and therefore it should be straightforward to diagnose these simply by doing IgG antibody studies for these two viruses.

Based on info above, I did the IgG testing for CMV and HHV-6. Is that not correct? My doc just told me I was supposed to do CMV Ab IgM and HHV Ab IgM instead.

Btw, these were my results, which I thought meant HHV-6 infection and that I need to treat with Valcyte?

HHV 6 IgG Antibodies ---- 1.59 High
index
Negative <0.90
Equivocal 0.90 - 1.10
Positive >1.10
 

ljimbo423

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This screenshot is from the Center for Disease Control in the U.S.-

Laboratory Testing


Laboratory Diagnosis of CMV Infection for People older than 12 Months
Serologic tests that detect CMV antibodies (IgM and IgG) are widely available from commercial laboratories. The enzyme-linked immunosorbent assay (ELISA) is the most common serologic test for measuring antibody to CMV.
  • A positive test for CMV IgG indicates that a person was infected with CMV at some time during their life but does not indicate when a person was infected. This applies for persons ≥12 months of age when maternal antibodies are no longer present.
  • Measurement of CMV IgG in paired samples taken one to three months apart can be used to diagnose primary infection; seroconversion (1st sample IgG negative, 2nd sample IgG positive) is clear evidence for recent primary infection.
 

sometexan84

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@Hip

So, two questions (+1 comment).....

1) Does that mean I should have tested the IgM in addition to the IgG? In which case, the results I shared above do not include enough data to mean anything?

2) The lab results didn't mention ELISA or IFA. Does it matter? Should I assume it's ELISA?

All I know is, these results from LabCorps came back as "out-of-normal range".
 

Hip

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1) Does that mean I should have tested the IgM in addition to the IgG? In which case, the results I shared above do not include enough data to mean anything?
As I understand it, Dr Lerner required both IgM and IgG to be high before he diagnosed chronic active HHV-6 infection in ME/CFS patients.

Whereas in his clinical trials, Prof Jose Montoya only required high IgG to diagnose chronic active HHV-6 infection in ME/CFS. Ref: 1

But Prof Montoya would combine EBV and HHV-6 together, so his criteria for active infection is = high EBV VCA IgG and high EBV EA IgG, as well as the simultaneous requirement for high HHV-6 IgG. Ref: 1 2




2) The lab results didn't mention ELISA or IFA. Does it matter? Should I assume it's ELISA?
I don't think it makes much difference. ELISA and IFA are similarly sensitive.



I am not sure I would call your HHV-6 IgG antibodies high though. You are 1.59 and the reference range for negative is < 0.9. So you are only just above the negative. Usually when I see high IgG antibody levels in ME/CFS patients, people are 16 times or more above the negative value.

For example, in my cytomegalovirus test, the reference range for negative is < 6.0 AU/mL, and my IgG antibodies were 206.8 AU/ml. That's 206.8 / 6 = 34 times higher than the negative value.



Have you checked for other viruses commonly linked to ME/CFS, enteroviruses (coxsackievirus B and echovirus) as well as herpesviruses (EBV, HHV-6 and cytomegalovirus)?
 
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sometexan84

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@Hip

Not yet on the enteroviruses. These are my results for the others...

HHV 6 IgG Antibodies ---- 1.59 High

Negative <0.90​
Equivocal 0.90 - 1.10​
Positive >1.10​

Cytomegalovirus (CMV) Ab, IgG ---- <0.60

U/mL 0.00-0.59​
Negative <0.60​
Equivocal 0.60 - 0.69​
Positive >0.69​
EBV (Ebstein Barr Virus)
Epstein Barr virus capsid Ab.IgM ---- <36.0

Negative <36.0​
Equivocal 36.0 - 43.9​
Positive >43.9​

Epstein Barr virus early Ab.IgG ---- H 30.1

Negative < 9.0​
Equivocal 9.0 - 10.9​
ositive >10.9​

Epstein Barr virus capsid Ab.IgG ---- H >600.0

Negative <18.0​
Equivocal 18.0 - 21.9​
Positive >21.9​

EBV Nuclear Antigen Ab, IgG ---- H 582.0

Negative <18.0​
Equivocal 18.0 - 21.9​
Positive >21.9​
 

sometexan84

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@Hip

On a side note, my current internal med doc has been trying to get me scheduled with an infectious disease physician and her referrals keep getting denied, across the board. They say "We don't deal with fatigue". But I really would like to go ahead and get tests done for other possible infections. I believe my doctor's referrals have said things like "treatment for mono, ebv, infections for fatigue"... something along those lines.
 

Hip

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Dr Lerner's criteria for active EBV are high antibody levels in the VCA IgM and/or EA IgG diffuse tests. Refs: 1 2

Your EA IgG is 30.1, and ref range for negative is 9. So you are slightly elevated, but I am not sure if it would qualify as high. You really need an ME/CFS doctor to interpret the results.

Note that:
EA = early antigen
VCA = virus capsid antigen (also denoted by CA)
EBNA = Epstein-Barr nuclear antigen


Infectious disease specialists are usually no good at doing ME/CFS viral testing, as they interpret results differently to ME/CFS doctors.
 

Learner1

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I agree. I've been to 2 infectious disease specialists and they couldn't find the infections that were destroying my health.

HHV6 is tricky. Usually patients have higher HHV6 titers but not always:

https://hhv-6foundation.org/patients/hhv-6-testing-for-patients

EBV is also tricky. You might want to try a PCR. Your values are high, but most docs would read them is past infection, which may not be right. I've attached some documents showing how tricky it may be to diagnose someone. And how Valcyte has successfully been given to patients with titers like yours, with reduction in symptoms.

You might also want to become familiar with Dr. Prustys most recent paper which shows how a nit quite fully active HHV6 can cause mitochondrial fragmentation (and fatigue). Other herpes viruses can be assumed to do this, too.

You don't need a fancy doctors. You need a cooperative one who will take the medical research you take him/her and prescribe Valcyte, which works on HHV6, CMV and EBV.
 

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Hip

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What do you base that on? The HHV-6 foundation explicitly states that ELISA is not sensitive enough to reliably differentiate between normal post-infection titers and pathological titers. (ref) Dr Montoya used IFA in his research (ref).
Interesting, I've never seen that statement from the HHV-6 Foundation before.

Generally when I've seen studies that examine the sensitivity of antibody tests, the order of sensitivity is this:
  • Neutralization test (various types of neutralization test: micro-neutralization test, plaque reduction neutralization test, cytopathic effect neutralization test).
  • EIA (enzyme immunoassay) and ELISA (enzyme-linked immunosorbent assay). ELISA is a specific type of EIA.
  • IFA (immunofluorescence assay, or immunofluorescence test), also called IFT, IF.
  • CFT (complement fixation test), also called CF.
Neutralization is the gold-standard most sensitive, followed by EIA/ELISA, with IFA being similarly sensitive to EIA, but IFA typically lagging slightly behind the sensitivity of EIA.

If you take a virus like coxsackievirus B, which is one of the hardest viruses to detect in chronic infections, only a neutralization antibody test can reliably detect it. This is what Dr Chia found.

EIA and IFA might sometimes detect chronic CVB, but will often miss it. And CFT is completely useless for chronic coxsackievirus B, and will never detect such chronic infections, as CFT is completely insensitive in the chronic infection context (CFT is only suitable for detecting acute infections).



I just Googled, and came across this old paper from 1996, which found ELISA was more sensitive than IFA. But maybe techniques have changed since then.
 
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Hip

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Maybe ELISA is more sensitive in detecting if a sample is positive for HHV-6 antibodies, but IFA is more precise in how elevated the titers actually are.
Could be, I guess.

It is unfortunate that the HHV-6 Foundation do not give study references, or give the source of their assertion that ELISA IgG only provides a yes/no qualitative answer, whereas IFA IgG provides more quantitative gradations in its answer.

I found this article which says:
ELISA may be run in a qualitative or quantitative format.

Qualitative results provide a simple positive or negative result for a sample. The cutoff between positive and negative is determined by the analyst and may be statistical. Two or three times the standard deviation is often used to distinguish positive and negative samples.

In quantitative ELISA, the optical density or fluorescent units of the sample is interpolated into a standard curve, which is typically a serial dilution of the target.
So I guess it depends on how the lab runs the ELISA test that determines whether it is qualitative or quantitative.



Looking at the HHV-6 tests that Dr Martin Lerner used (page 4 of this document), it says for both HHV-6 IgM and IgG, Lerner used LabCorp.

LabCorp's current HHV-6 IgG test is ELISA.

And the HHV-6 Foundation say:
Quest Diagnostics and ARUP Laboratories are two of the only known laboratories in the USA to perform testing by IFA methodology.
Which confirms that LabCorp does not offer HHV-6 IFA.



It would be interesting to write to LabCorp and ask whether their HHV-6 IgG ELISA is qualitative or quantitative. But I've tried to contact LabCorp before (as a non-customer from outside the US), and they have unfortunately never replied to my emails.
 

Cipher

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@Hip It seems like the HHV-6 foundation thinks quantitative ELISA is inferior to IFA:

ELISA tests results are reported as a single number (e.g. 2.1 or 5.5) and for complicated reasons they are not as reliable as IFA tests for determining whether you have highly elevated antibodies. This assay was designed as a qualitative test (yes/no answer) and is not recommended for monitoring your HHV-6 antibody levels over time or during treatment. If the ELISA result states that you have >1 and are “positive” this usually just means that you have been EXPOSED to the virus, not that you have an active viral infection. This is a meaningless result since everyone over the age of two has been exposed to HHV-6. A high number (above 4 or 5) MAY be significant, but again, this all depends on the laboratory and the kit they use. You can ask your doctor to find out from the lab how your ELISA result compares to that of normal controls in order to interpret your value. If your value is at the high end, then consider getting the IFA test mentioned above to confirm possible reactivation.
(Source)
 

Hip

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It seems like the HHV-6 foundation thinks quantitative ELISA is inferior to IFA:
I've just updated my roadmap to include a note in the HHV-6 section saying that the HHV-6 Foundation think IFA is better than ELISA, for IgG tests (but for IgM they say either IFA or ELISA is fine).

I wonder if this also applies to other herpesviruses like cytomegalovirus?
 

Cipher

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I've just updated my roadmap to include a note in the HHV-6 section saying that the HHV-6 Foundation think IFA is better than ELISA, for IgG tests (but for IgM they say either IFA or ELISA is fine).
:thumbsup:
I wonder if this also applies to other herpesviruses like cytomegalovirus?
It might be worth a shot contacting the HHV-6 foundation to learn more about their reasoning regarding ELISA vs IFA, their contact info can be found here.
 

Hip

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I got a fast and very interesting response from the HHV-6 Foundation.

Here is the email I sent them:
Dear Sir

I read with interest your advice that for the purpose of detecting a chronic smoldering HHV-6 infections, you recommend IFA rather than ELISA IgG antibody tests, as the former is quantitative, whereas the latter is only qualitative (yes/no answers only).

I'd like to ask: would this advice also apply to other herpesviruses like cytomegalovirus? In the context of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) for example, this disease is associated with persistent smoldering infections of HHV-6, EBV and cytomegalovirus (as well as smoldering enterovirus infections of coxsackievirus B or echovirus).

So when testing for IgG antibodies in chronic CMV and EBV infections, is IFA also advised?

I've read that ELISA can be set up either in a qualitative mode or a quantitative mode, so I presume labs such as LabCorp who offer ELISA antibody tests are using the qualitative mode.

You may be interested that Dr John Chia (member of the Enterovirus Foundation) has discovered that for detecting smoldering enterovirus infections in ME/CFS, only neutralization-type antibody tests are sensitive enough (like plaque reduction neutralization tests, or micro-neutralization tests). I understand that neutralization is the gold-standard in terms of sensitivity, being more sensitive than IFA and ELISA.

However, I've never seen a neutralization antibody test for herpesviruses. Would you know why that is?

Thank you very much for your help.


Here is the HHV-6 Foundation's reply:
It would be advised for CMV but I am not aware that they are available. For EBV, the EBV early antigen test can differentiate between active and latent infection, because those early antigen antibodies disappear quickly so if you have them, you know you are either active or have had a recent infection.

Unfortunately there is no commercially available HHV-6 Early Antigen antibody test.

There is a research assay available for HHV-6A Immediate Early antibodies, and it has shown elevated antibodies in MS patients, but it is not available commercially yet.

Yes, we are aware of Dr. Chia’s view on neutralization only antibody tests. Most virologists/ID physicians do not share is view on this being the only antibody test that is useful for enteroviruses. We don’t have an opinion and have a lot of respect for Dr. Chia.

Unfortunately, no lab has thought it important enough to develop better antibody tests for HHV-6 that could differentiate between active and latent infection.

I hope this answers your questions.
 

sometexan84

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@Learner1

And how Valcyte has successfully been given to patients with titers like yours, with reduction in symptoms.
Valcyte vs Valtrex?

Been on Valtrex (500mg 3x/day) for 1 month now. I feel decent energy levels the majority of the days. But in past 30 days (since starting Valtrex), there have been 3 times where I was exhausted. Each time, the exhaustion lasted 24-48 hrs.