Chronic Epstein-Barr Virus Infection or Something Else?
- Christine Daecher, DO
- Feb 26
- 5 min read
Is chronic Epstein-Barr infection real? Does having a history of Epstein bar virus infection increase risk for other chronic diseases? Read on to learn more about chronic Epstein-Barr virus (EBV) infection.
About EBV
EBV is a virus that is part of the herpes virus family. Of all the viruses, herpes viruses have a tendency to be chronic and may occasionally replicate and resurface at another time. Examples include getting cold, sores occasionally or shingles. Different herpes viruses cause each of these conditions.
The average person has 5-6 chronic viruses in their body. EBV is a ubiquitous virus that infects 95% of the world population at some point in life, with most of us having been infected with this virus by our early 20s. Considering how common this virus is and how uncommon it is for a person to have possible chronic conditions related to it, clinicians and researchers have tried to solve the puzzle of chronic EBV.
Testing EBV Antibodies: What Does It Mean?
For a number of decades, it has been en vogue to test patients with chronic fatigue and other symptoms for EBV antibodies. Two main types of antibodies that tend to be tested are EBV IgM and EBV IgG. Results produce titers (spelled titer or titre). An elevated level of EBV IgM signifies a new or acute illness. It is elevated when the body first recognizes the EBV virus and starts to make initial antibodies to attack it. An elevated EBV IgG titer level signifies prior infection and possible chronic infection. Our discussion will focus on the presence of high EBV IgG.
Chronic EBV may be either a chronic infection, post-acute sequelae, or both. It is often impossible to know which condition exists, and it may be impossible to know proof-positive that a person's chronic symptoms are from EBV or something else.
Chronic infection is easy to understand and represents a virus that is continually active and replicating itself in the body. Postacute sequelae involve the continued immune system, dysregulation, and inflammation. This may be a result of the cross-reactivity of antibodies or persistent viral fragments triggering persistent immune activity. Back to our antibodies...very high EBV IgG titers may be normal findings if EBV viral load (VL) is not elevated, or it may be a sign of post-acute sequelae. It may be impossible to differentiate.
EBV IgG Subtypes, Autoimmunity, and Cancers
To further understand EBV IgG, research has focused on different subtypes of this antibody. One particular subtype, when high EBNA1-specific IgG, has been associated with the development of multiple sclerosis (MS). This antibody appears to corrupt the cells of the immune system, which results in them crossing the blood-brain barrier. High EBNA1-specific IgG can be found in a person at least 10 years before MS presents. Studies evaluating IFNβ therapy in persons with MS have shown a reduction in proliferative T-cell responses to EBNA1-specific IgG1. This is to say that treatment (less inflammation) reduces EBNA1-specific IgG.
Another EBV IgG subtype, EBV early antigen D IgG, is found at high titre levels in persons with lupus (SLE). Many SLE specialists believe that prior EBV infection must exist to develop SLE (lupus). This antibody has also been found in some cases of an inflammatory condition of the eye called uveitis. With uveitis, the elevation appears to represent a reactivation of the virus as clinical improvement occurs with antiviral medication.2
Other autoimmune conditions, including rheumatoid arthritis and Sjogren syndrome. I've also shown associations with prior EBV infection. Studies looking for the presence of EBV virus in the gastrointestinal tract also found that the virus is present in 44% of normal colon mucosa, 55% of cola mucosa with Crohn's disease, and 64% of Cours mucosal with ulcerative colitis. Interestingly, EBV is not found in healthy gastric mucosa but is present in 46% of gastric lesions/inflammation.3 Further, concerning gastric cancers, H. pylori infection appears to start inflammation of the gastric mucosa by the recruitment of EBV virus in infected gastric cells resulting in EBV replication and leading to worsening gastric inflammation. 3 This is an example of reactivation of the virus in a tissue reservoir.
Left, shows colon mucosa of ulcerative colitis. Right, shows gastric mucosa with gastric cancer. The dark spot in each image is a cell with EBV RNA staining. Cite: Ryan JL, et al.
Subtype EBV Viral Capsid Antigen IgG (EBV VCA IgG) has been found in a significant increase in persons with gastric cancer. This was especially noted in young females who were H. pylori-negative (see a blog post about this infection).4
EBV has also been associated with an increased risk of developing Hodgkin's lymphoma, Burkitt's lymphoma, and nasopharyngeal cancer.
Should we test for EBV IgG levels?
We are back to our original question about any value of testing for the presence of EBV antibodies. The problem is that a positive result might not add any helpful information. Even when different EBV IgG subtypes are tested, elevated titers may not add value. Even the best research that is available on EBV only shows associations of other conditions, but not absolute proof. Remember, 95% of the population will have the presence of EBV IgG, signifying that they have been infected at some point in their lives.
References:
1. Comabella M, Kakalacheva K, Río J, Münz C, Montalban X, Lünemann JD. EBV-specific immune responses in patients with multiple sclerosis responding to IFNβ therapy. Mult Scler. 2012 May;18(5):605-9. doi: 10.1177/1352458511426816. Epub 2011 Oct 21. PMID: 22020417.
2. Boonsopon S, Maghsoudlou A, Kombo NE, Foster CS. A therapeutic trial of valganciclovir in patients with uveitis and positive Epstein-Barr virus early antigen D IgG titers. Eur J Ophthalmol. 2016 Jan-Feb;26(1):30-5. doi: 10.5301/ejo.5000673. Epub 2015 Sep 2. PMID: 26350994.
3. Ryan JL, Shen YJ, Morgan DR, Thorne LB, Kenney SC, Dominguez RL, Gulley ML. Epstein-Barr virus infection is common in inflamed gastrointestinal mucosa. Dig Dis Sci. 2012 Jul;57(7):1887-98. doi: 10.1007/s10620-012-2116-5. Epub 2012 Mar 13. PMID: 22410851; PMCID: PMC3535492.
4. Wang Z, Lv Z, Ding H, Xu Q, Sun L, Jing J, Yuan Y. Role of serum EBV-VCA IgG detection in assessing gastric cancer risk and prognosis in Northern Chinese population. Cancer Med. 2018 Nov;7(11):5760-5774. doi: 10.1002/cam4.1792. Epub 2018 Oct 10. PMID: 30306734; PMCID: PMC6246934.
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