Chronic Epstein Barr Virus - recurring positive IgM (I am not the patient)

Diwi9

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Hi folks - I have a girlfriend who is dealing with a slew of symptoms and has had IgM positive lab tests in 2019 and 2022. Her current symptoms include low grade fever, swollen lymph node, tonsilitis, fatigue, and sleep disturbance. She has some questions I list below that I thought could be crowd-sourced here given the wealth of knowledge and complications this community has with EBV.

She is a sort of medical anomaly given her history:

College - EBV injection with full-blown mononucleosis, resolved after a number of weeks

2006 - Cervical spine injury (C3-C6) + lumbar spine from motor vehicle accident

2011 - Breast cancer (ER/PR+ her2-, stage 3), chemotherapy

2012 - Stroke from Tamoxifen

~2015 - Epiploic appendagitis (CT scan), no intervention, just watched

2017 - Diagnosed with abnormal reflex responses in colon (diagnosed by Mayo)

2018 - Hospitalization for 105 fever, extreme fatigue and headache, given antibiotics, no additional stroke activity per brain imaging

2019 - Oncology screening for potential leukemia based on recurrent low grade fever, swollen lymph nodes - exclusion testing included EBV panel, tested IgM positive but no intervention of follow up for EBV


2022 - Fever, severe abdominal pain, tonsillitis, grape-sized lymph node on neck, EBV panel IgM results positive again
Some questions.:

Can EBV be progressive and is there a fatal form of EBV infection? If so, can this form of EBV also arise from reactivation, or just from acute/severe initial infection? Is someone who has reactivation and IgM positive infectious to others?

I'm attaching a copy of her labs. Unfortunately, there are no lab value available, only positive or negative values.

Tagging some knowledgeable folks for potential input: @Pyrrhus @Hip @Learner1 @Manuel

IgM.jpeg Screen Shot 2022-01-09 at 2.19.04 PM.png
 

Hip

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Can EBV be progressive and is there a fatal form of EBV infection?
There is chronic active Epstein-Barr virus infection (CAEBV), which can eventually be fatal if not treated, but it is a rare illness.

The link says:
Chronic active Epstein-Barr virus infection (CAEBV) is diagnosed based on the symptoms, a clinical exam and high EBV DNA in the blood which persists for at least 3 months. A test known as a quantitative PCR test is used to measure the amount of EBV DNA.
CAEBV is treated with hematopoietic stem cell transplantation.
 

Diwi9

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@Hip - I thought it was a major disservice by her laboratory to not indicate values, only positive or negative.
 

Diwi9

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@Hip - Do you know if it common for PCR testing for EBV. Despite many PwME having problems with EBV, I've never heard of any of us receiving a PCR test...only antibody testing.
 

Hip

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Do you know if it common for PCR testing for EBV. Despite many PwME having problems with EBV, I've never heard of any of us receiving a PCR test...only antibody testing.
ME/CFS patients are typically negative on PCR blood tests for ME/CFS viruses, including EBV, although you do sometimes get positive PCR results.

This is because in ME/CFS, the virus is not found much in the blood, but may be in other organs or tissues.

So this is why antibody testing is used in ME/CFS, because the virus is not in the blood.

PCR directly detects the virus itself, whereas antibody testing detects the virus more indirectly, by the immune response to the virus. If the virus is hiding in the tissues, you can detect it indirectly by antibody testing.


So there is a difference between EBV-associated ME/CFS and CAEBV. In the former, blood PCR is often negative, even though EBV antibodies are high, suggesting that there might be an EBV infection hidden in the tissues. In the latter, PCR is positive, because the virus is actually in the blood.
 

Diwi9

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@Hip - It sounds like viral shedding only occurs then when the virus is in the blood. When you mention EBV-associated ME/CFS and the virus being active in tissue, it seems that some of this viral material would still be found in the blood...I know that is what Dr. Ron Davis has said in the past. But, perhaps only in very small quantities, or viral components...so actually getting a positive PCR hit would be a crapshoot.

I wonder how often one is PCR positive if they are IgM positive? Is there a reason we don't just automatically start with PCR testing--cost-prohibitive? Anyone can answer these questions, I'm not trying to just target you, @Hip. I'm just generally curious about these things as we seem to be having a myriad of problems with antibody tests for Covid these days.
 

Hip

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When you mention EBV-associated ME/CFS and the virus being active in tissue, it seems that some of this viral material would still be found in the blood...I know that is what Dr. Ron Davis has said in the past. But, perhaps only in very small quantities, or viral components...so actually getting a positive PCR hit would be a crapshoot.
Yes, that's right.

We actually have more PCR data for enterovirus-associated ME/CFS, because in his thoroughness, Dr Chia spent a lot time exploring various forms of viral testing in his ME/CFS patients.

When Dr Chia PCR tested the blood of literally thousands of his enterovirus ME/CFS patients, using the most sensitive PCR available, he would sometimes find the patients were positive by blood PCR, but on the next test the same patient might be negative again. When the same patient was repeat tested, Dr Chia found most of the time they were negative, but you'd get a positive result appearing sometimes.

From this pattern, Dr Chia concluded that there are very low levels of virus in the blood, just below the threshold of detection of the most sensitive PCR tests.



I wonder how often one is PCR positive if they are IgM positive? Is there a reason we don't just automatically start with PCR testing--cost-prohibitive?
That is a question I've always want to know the answer to. Since high IgM represents a first-time acute infection, or a viral reactivation, you might expect those with high IgM to have some virus in the blood, and so be blood PCR positive.



Of course EBV interpretation is more complicated that other viruses, as you have not one but three EBV antibody types (EBNA, VCA and EA), and for each of those three, you have the IgM and IgG versions. So that's 6 parameters altogether.
 
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Hello - I am the patient @Diwi9 is posting about - went ahead and joined here, as I feel like I fit in the category of "I'm investigating (I have ME/CFS-like symptoms)." I really appreciate this discussion, thank you!

What I am most curious/anxious about right now, is if it is common to have IgM+ results with reactivation, other than in cases of CAEBV - and also, if it is possible to get CAEBV in a reactivated case, or only in the original acute EBV infection. I originally had mono 25+ years ago. I'm still unclear on that part...

I am hoping to see my immunologist this week and will have lots of questions. Also wondering if there are things I should be asking him about that might not occur to me, as this whole world is new to me and in addition to feeling really sick, I'm feeling pretty overwhelmed.

Thank you so much for any insight.
 

Hip

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Hello - I am the patient @Diwi9 is posting about - went ahead and joined here, as I feel like I fit in the category of "I'm investigating (I have ME/CFS-like symptoms)." I really appreciate this discussion, thank you!
Hello Vandy, welcome to Phoenix Rising.



is possible to get CAEBV in a reactivated case, or only in the original acute EBV infection. I originally had mono 25+ years ago. I'm still unclear on that part.
I don't really know the answer to that question, but this paper suggests CAEBV can occur after a reactivation of EBV:
Rare patients who become infected with EBV, or reactivate EBV, develop disease that does not resolve.

Some of these patients develop fulminant infectious mononucleosis and die within days or weeks of primary infection. Others develop a more chronic course with persistent or intermittent infectious mononucleosis-like symptoms including fever, persistent lymphadenopathy, splenomegaly, and EBV hepatitis.

These patients are unable to control EBV infection and have infiltration of tissues by EBV positive T, NK, or less often B cells. They have markedly elevated levels of EBV that persist in the blood. This entity is referred to as chronic active EBV (CAEBV) disease.
However, CAEBV is rare, its annual incidence is something like 1 in a million people. Whereas the annual incidence of ME/CFS is around 150 in every million people.


There is a story in this post of a CAEBV patient who was cured of her CAEBV within 3 days of getting a rituximab infusion. Rituximab destroys the B-cells in which EBV lives.
 

Learner1

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Hello - I am the patient @Diwi9 is posting about - went ahead and joined here, as I feel like I fit in the category of "I'm investigating (I have ME/CFS-like symptoms)." I really appreciate this discussion, thank you!

What I am most curious/anxious about right now, is if it is common to have IgM+ results with reactivation, other than in cases of CAEBV - and also, if it is possible to get CAEBV in a reactivated case, or only in the original acute EBV infection. I originally had mono 25+ years ago. I'm still unclear on that part...

I am hoping to see my immunologist this week and will have lots of questions. Also wondering if there are things I should be asking him about that might not occur to me, as this whole world is new to me and in addition to feeling really sick, I'm feeling pretty overwhelmed.

Thank you so much for any insight.
Hi @Vandy

I've attached some articles that should be helpful. You might want to particularly read the one called "chronic Epstein Barr" and read about how the virus can create a chronic infection with a variety of characteristics - I think you can skip the ME/CFS for now and just pay attention to the description of how the virus behaves and the ways it can become chronic.

The two on diagnosis both have charts describing how to diagnose EBV using serological (antibody) testing, a method that is favored because it allows discrimination of stages of the virus in IMMUNOCOMPETENT patients.

Screenshot_20220110-204324.png

Screenshot_20220110-214502.png

The serological testing I've had included VCA, EA, and EBNA. Yours doesn't specify, but I think it might be EBNA and VCA. Looking at the orange chart, your results seem to indicate late primary infection or reactivation with a need for further investigation. The second chart says Undetermined, with a need for further investigation. I'm a cancer survivor, too, and, knowing that EBV is linked to several cancers and has been known to reactivate after chemotherapy, I'm extremely puzzled as to why, with your history, your doctors did not investigate further, especially since one can assume that your immune system is less than robust.

The comment at the bottom of the second chart suggests several choices for further investigation. My doctor, who was an AIDS doctor for many years and is used to nasty infections and dysfunctional immune systems uses PCR testing, which finds the viral DNA, as a second method.

However, given that you have had positive IgM on multiple occasions, it seems pretty sure that you have a chronic EBV infection. Though this may not be alarming to your doctors, since over 90% of the population has had EBV, it should be alarming as EBV can cause several cancers, trigger multiple kinds of autoimmunity, compromise the immune system and create one or more unpleasant symptoms, including fatigue, weakness, brain fog, swollen lymph nodes, fever, etc.

If this is the case, why are your doctors not treating the EBV? Valacyclovir would be a decent first choice for treatment, but other drugs like famciclovir and valganciclovir could be considered.

A long term, chronic EBV infection can cause significant immune dysfunction/deficiency. This can create an opportunity for other infections, like the 7 others in the herpes family, particularly cytomegalovirus and HHV6 if you don't have symptoms suggestive of any of the others. Have you been tested for these? If you have them, it might dictate which drug would be best. You might look for other infections, like chlamydia or mycoplasma pneumoniae, Cocksackie viruses, Parvovirus B19, and Lyme and co-infections if you spend time outdoors in an area known to have Lyme, etc

An investigation of your immune system would be worthwhile as well. Since you don't seem to have kicked the EBV on your own, and you have a history of cancer, an investigation of your immune system night be useful - immunoglobulins with subclasses, NK cell function, a CD57 panel, cytokines, etc.

And, EBV is also notorious for causing a myriad of types of autoimmunity. If you have unexplained symptoms of any type, you might look into testing for various autoimmune antibodies which explain some of your symptoms. Many doctors will start with antinuclear antibodies (ANA) but there are a good many of us with a negative ANA and a lot of weird antibodies.

In answer to @Diwi9 's original questions, yes, EBV can lead to progressive conditions that lead to fatality. It is not something to be ignored.

As for @Hip"s assertion that Rituximab can cure chronic EBV, I'd be extremely skeptical. My doctor prescribes Rituximab to patients only after beating back infections with anti-virals and antibiotics - otherwise, without antibodies, a patient could be very vulnerable to an Infection they can't fight. I successfully had Rituximab beat back autoimmunity, but I had another herpesvirus, HHV6, reactivate after my COVID vaccine last year..unless EBV is that different about where it hangs out, I'd be surprised that it would be killed off by Rituximab. The chronic EBV article says EB hides out in CD21 cells and Rituximab kills off CD20 cells.

Best of luck with your investigation, but I'd suspect the sooner you get a good antiviral on board, the sooner you'll find improvement.
 

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@Learner1 Thank you so much for all of this. Too exhausted to read the attachments tonight, but will definitely review before appointment with immunologist.

I've been having autoimmune illness symptoms for years, without definitive diagnosis. I was last tested for ANA in 2019 and was negative. As for Rheumatoid Arthritis I am positive for CCP but negative for RA factor (also last tested in 2019), and don't have enough other clinical symptoms to have gotten an RA diagnosis officially, but my doctors have mentioned it as "possible." I cannot count the number of times I have been tested for leukemia because of symptoms, and high risk due to radiation/chemo, but those tests have always been negative.

I'm really angry that my oncologist didn't follow up on positive EBV IgM in 2019. She'd ordered dozens of tests at that time, and I think was more focused on the cancer-related ones (including PET scan) due to recurrent fevers and lymphadenopathy. I wasn't even aware of the positive IgM result until mid-2021, when my new immunologist noticed it while reviewing my medical record. His advice at the time was to get another EBV IgG/IgM antibody test if I experienced another episode of fever and lymphadenopathy, which was just this past week.
 
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@Lerner1

And yes...I definitely suffer from brain fog, from chemo, from stroke, and from who knows what else. I wish there was an edit function on comments here (or is there one that I'm just overlooking?).

Yes, the tests I got were VCA and (I believe) EBNA - attaching a better screenshot here. The rest of my bloodwork from the same day was normal except for slightly low .GFR and slightly low MPV. I was shocked that WBC was well within normal range, considering my symptoms.

Should have mentioned too that my 2019 CCP wasn't outrageously high at 42.7 U, standard range is <20.0 U.

VandyEBV.PNG
 

Hip

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As for @Hip"s assertion that Rituximab can cure chronic EBV, I'd be extremely skeptical.
That is not what I was saying. I just referred to Fluge and Mella's observation of one particular case of CAEBV, where rituximab cured her condition in days.

Whether this rituximab treatment would generally work for CAEBV, I don't know. We certainly know that rituximab is not generally beneficial for ME/CFS.

The normal treatment for CAEBV is hematopoietic stem cell transplantation.
 

Learner1

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That is not what I was saying. I just referred to Fluge and Mella's observation of one particular case of CAEBV, where rituximab cured her condition in days.

Whether this rituximab treatment would generally work for CAEBV, I don't know. We certainly know that rituximab is not generally beneficial for ME/CFS.

The normal treatment for CAEBV is hematopoietic stem cell transplantation.
I think you'd have a hard time getting that treatment outside of Japan.

I think this is what you're referring to, as this treatment is anything but normal:

"Abstract

Chronic active Epstein-Barr virus infection (CAEBV) is a prototype of the EBV-associated T- or NK-cell lymphoproliferative diseases, which also include hypersensitivity to mosquito bites and severe-type hydroavacciniforme. The manifestations of CAEBV are often self-limiting with minimum supportive care or only prednisolone and cyclosporine A with or without etoposide. However, allogeneic hematopoietic stem cell transplantation (HSCT) is the only cure, without which patients with CAEBV die within several years. A severe hypercytokinemia and hemophagocytic syndrome, which may occur suddenly, often results in a fatal clinical course. At out institute, we have established a 3-step strategy, including allogeneic HSCT, for the treatment of CAEBV. Seventy-nine patients with CAEBV and related diseases have been treated to date. The 3-year overall survival rate (3y-OS) is currently 87.3 ± 4.2% after planned allogeneic HSCT. However, 3y-OS in patients with uncontrolled active disease is only 16.7 ± 10.8%. To maximize survival rates with minimized late sequelae, we recommend earlier initiation and completion of the 3-step treatment without watchful waiting."

https://pubmed.ncbi.nlm.nih.gov/28210942/

I have had a couple of my more Maverick doctors suggest I look into stem cells. However, as a cancer survivor, It was decided that stem cells could possibly provoke a new cancer, which was an undesirable outcome.

I think one would also have to decide if one were sick enough like these particular patients who sounded like they were having cytokine storms. As the other article I posted said, there is a variety in types of CAEBV, which is a very extreme form of EBV. In this case, it sounds like @Vandy has untreated EBV, so it's chronic, not necessarily CAEBV.
 

Learner1

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I'm really angry that my oncologist didn't follow up on positive EBV IgM in 2019. She'd ordered dozens of tests at that time, and I think was more focused on the cancer-related ones (including PET scan) due to recurrent fevers and lymphadenopathy. I wasn't even aware of the positive IgM result until mid-2021, when my new immunologist noticed it while reviewing my medical record. His advice at the time was to get another EBV IgG/IgM antibody test if I experienced another episode of fever and lymphadenopathy, which was just this past week
I have been in the cancer survivor system in 2 major US cities, both known for their high quality cancer care. I was sleeping 16 hours a day I couldn't see straight or think straight in 2016, and went to over a dozen MDs and the cancer community saying I thought there was something wrong with my immune system and could someone please help me find answers. I got gaslighted, had head shaking, and the best offer I got was to go to a pain clinic when I wasn't in pain.

Meanwhile, my naturopathic doctor was busily running standard LabCorp tests and found the HHV6 and cytomegalovirus and enough wrong with my immune system that I sought out a top specialist in another state, who found the EBV that everyone else had missed by doing a PCR test as well as 6 other chronic infections and significant immunodeficiency. Treating each of these has greatly helped.

Feeling stable, I moved across the country, to be turned down by 6 primary care practices sight unseen, because "you're too complex." Both the old and the new cancer survivorship clinics told me that cancer survivors have real problems in getting good care because the primary care doctors just don't understand the complexity of what we're dealing with and the cancer people think they're done with us because they've saved our lives by curing the cancer. Meanwhile, the rest of the medical system is so super specialized that the kidney doctors only look at kidneys, the neurologists only look at brains, the cardiologists only look at hearts, etc.

I've also found immunologists which tend to be a strange lot. Most of them that we have access to are allergy specialists, so dealing with a patient with a chronic virus and even immunodeficiency isn't in their normal realm, which is allergy shots and treating asthma. There are cancer immunologists, but they don't want to deal with a likes of us, they tinker with the immune system to get it to kill cancers. Then, there are the AIDS immunologists, which, ironically, can be the best for us, because they have seen immune systems go haywire with all kinds of weird opportunistic infections and immunodeficiency, so they are better equipped to help us, although usually we can't see them.

Then there are infectious disease doctors. I have yet to have one help me. They seem to be more interested in rare tropical diseases that we get on vacation or bacterial infections, I guess, but they seem to be lousy at dealing with EBV, HHV6, and CMV Not to mention prescribing an antiviral. I had one helpfully test me for tuberculosis and syphilis, neither of which I had any reason to suspect I had, But miss the EBV.

Rheumatologists are also a strange lot. I don't know what they do. I wasted a lot of time waiting for appointments with one only to have her fire me when she couldn't figure out how to help me. She also missed the EBV, refused to look at my HHV6 and CMV, and couldn't find the multiple types of autoimmunity that I had. A lot of them put people on immunosuppressive drugs that lead to leukemia and lymphomas.

So, I think the best doctor is one who cares about your symptoms, is curious, and willing to entertain more oddball diagnoses And is willing to look at any scientific paper you bring thoughtfully and provide solutions.

Given what you have shared, it seems that you have had an EBV infection that your body has not cleared. You need treatment. Once my EBV was found, my doctor wanted to put me on 3g valacyclovir (Valtrex) daily, but my insurance denied that dose and would only let me have 2g and because I also had active HHV6 and CMV, valganciclovir was the better drug, and he put me on 4 450mg pills daily for 12 months and 2 450mg daily for another 8 months until I had 4 successive negative PCR tests.

He also supported my immune system with low dose naltrexone (4.5mg) and intravenous immunoglobulins, which I still get every three weeks.

I've been having autoimmune illness symptoms for years, without definitive diagnosis. I was last tested for ANA in 2019 and was negative. As for Rheumatoid Arthritis I am positive for CCP but negative for RA factor (also last tested in 2019), and don't have enough other clinical symptoms to have gotten an RA diagnosis officially, but my doctors have mentioned it as "possible." I cannot count the number of times I have been tested for leukemia because of symptoms, and high risk due to radiation/chemo, but those tests have always been negative.
EBV is notorious for triggering autoimmune disease. This, in addition to the cancer causing potential for EBV, is why treating it earlier rather than later is wise.

I've also attached a list of antibody tests collected from patients on this forum. EBV is not specific in what it triggers, so you might look through the list and see if you have any sorts of symptoms associated with the antibodies. If you're lucky, you get well recognized antibodies that doctors feel comfortable treating. If you're really unlucky you can end up with autoimmune encephalitis which has killed patients. Somewhere in between are those of us with autoimmune POTS which no US lab tests for, but that a good German one does, and then US doctors refuse to recognize it because it wasn't run in the US...

If I were in your shoes, I would take your previous test results, the orange chart I posted above, and talk to your immunologist, and ask to be put on valacyclovir while being tested for other herpes family viruses, with both antibody and PCR tests. I would also ask for a thorough look at your immune system, including immunoglobulins, NK cell function, CD4/CD8. And, if this doctor refuses, I would be persistent and finding a doctor who will help you, whether it's in internal medicine doctor or one of the other ones that I listed.

After that is accomplished, I would look at antibody testing and see what's going on. If you have multiple nasty antibodies that are causing a significant problems, there are some specialists who would prescribe IVIG for a while, treat any infections they can possibly find, and then prescribe a course of rituximab, which is about a year process, which can wipe out the B cells causing the bad antibodies, before letting them eventually grow back, hopefully not producing antibodies. This strategy helped a few of us. But there's a lot of other work that must happen first.

You deserve help and to the bottom of this.
 

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Hip

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As well as Valtrex, a more experimental option for treating EBV-associated ME/CFS is spironolactone.

One study found spironolactone 25 mg daily resulted in 31% of EBV ME/CFS patients achieving full remission, and 69% observing improvements in their ME/CFS symptoms. See this post.