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Epstein-Barr

Epstein-Barr

Epstein-Barr virus (EBV) is part of the Herpes family of viruses.  There are eight separate viruses within this family: Herpes simplex 1 and 2 (HV 1, HV 2), Varicella (HV 3), EBV (HV 4), Cytomegalovirus (HV 5), Herpes virus 6 (HV 6), Herpes virus 7 (HV 7), and Kaposi sarcoma-associated virus (HV 8) (1).  HV1 and 2 are most commonly associated with oral and genital herpes.  Varicella causes chickenpox and shingles and CMV causes CMV mononucleosis, which is similar to EBV mononucleosis but is often less severe. HV6 and HV7 are most commonly associated with roseola infantum.  HV8 is not a known cause of acute illness but may cause Kaposi sarcoma and AIDS-related non-Hodgkin lymphomas. (1)

Infection and Transmission

All herpes viruses can remain latent within the body and EBV infects the B cells of the immune system.   EBV spreads primarily through body fluids, most commonly through saliva (3); it can also be transmitted through sexual contact, blood transfusions, and organ transplants (3).  EBV does not survive on surfaces but it “can be spread by using objects, such as a toothbrush or drinking glass that an infected person recently used. The virus probably survives on an object at least as long as the object remains moist.” (3)

An infected person can shed the virus for weeks before symptoms appear and “if the virus reactivates, (a person) can potentially spread EBV to others no matter how much time has passed since the initial infection.” (3) People with reactivated infections may also be able to transmit EBV to other people even if they themselves do not have active symptoms. (1)

Symptoms of Acute Infection

Half of children are infected with EBV before the age of 5 (2) and “EBV infections in children usually do not cause symptoms, or the symptoms are not distinguishable from other mild, brief childhood illnesses.” (3)

Symptoms of infectious mononucleosis develop most often in older children and adults and include fever, sore throat (pharyngitis), and lymph node swelling (adenopathy). (2)  The lymph node swelling is usually symmetrical, can include any group of lymph nodes, and may be the only symptom (2) Patients may also experience enlargement of the spleen and/or liver, swelling around the eyes, and rash.

The typical symptoms of acute infectious mononucleosis can be similar to those of other infections, and patients with this presentation should also be evaluated for primary HIV infection, cytomegalovirus infection, “toxoplasmosis, hepatitis B, rubella, or atypical lymphocytes associated with adverse drug reactions.” (2)

Complications of Acute Infection

Patients typically recover completely from EBV mononucleosis but fatigue can last for months after other symptoms resolve. (2, 3) Acute complications of the infection are rare but may be significant and can include:

  • Neurologic complications:encephalitis, seizures, Guillain-Barré syndrome, peripheral neuropathy, viral meningitis, myelitis, cranial nerve palsies, and psychosis
  • Hematologic complications: granulocytopenia, thrombocytopenia, hemolytic anemia
  • Splenic rupture
  • Respiratory complications: upper airway obstruction due to adenopathy
  • Hepatic complications: elevated aminotransferase levels, jaundice (2)

Chronic Infection Concerns

In addition to causing infectious mononucleosis, EBV is known as a potential cause of hepatitis, encephalitis, nasopharyngeal carcinoma, Hodgkin lymphoma, and Burkitt lymphoma (1, 2).  While EBV may remain latent for many people, significant research is being done into links between EBV and many autoimmune diseases.  A search of the NIH website for research done in just the last 5 years showed studies linking EBV as a potential cause of the development and exacerbation of multiple sclerosis (4, 5, 6), lupus (5), rheumatoid arthritis (7, 8), oral lichen planus (8), Sjögren’s syndrome (7, 9), Hashimoto’s and Grave’s diseases (autoimmune thyroid diseases) as well as possibly primary thyroid lymphoma (10).  “Autoimmune liver diseases (AiLDs), including autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC), have a potential causative link with EBV” (11) as do “interstitial pneumonia, malignant lymphoma, and coronary aneurysm.” (12)

The findings of a 2015 study indicated that EBV infections can become life-threatening in rare cases, but in contrast, “a range of other EBV-positive malignancies of lymphoid or epithelial origin arise in individuals with seemingly intact immune systems through mechanisms that remain to be understood.” (13) This indicates that EBV may cause significant immune disruption, including cancers, in otherwise immune healthy patients, through routes and interactions with other factors that we have not yet identified.  Given that the vast majority of the population has been infected with EBV but not everyone develops these conditions, we know that EBV infection alone is not the cause.  However, we also do not know what the characteristics are that would cause any individual person to go on to develop one of these conditions with EBV as one of the causative factors.

Diagnosis

Diagnosis of acute infectious mononucleosis is based on symptoms and signs and a positive heterophile antibody (monospot) test. Patients should know that “heterophile antibodies are present in only 50% of patients less than 5 years old and in about 80 to 90% of adolescents and adults with infectious mononucleosis.” (2) This test may also give a false-positive result in patients with acute HIV infection. (2) If there is high suspicion of mono but a negative monospot, it is worth repeating the test after 7 to 10 days, as the antibody levels rise in the 2nd and 3rd weeks of illness. (2) A complete blood count may also show atypical lymphocytes; it is important to know that “atypical lymphocytes may also be present in HIV or CMV infection, hepatitis B, influenza B, rubella, or other viral illnesses… however, very high atypical lymphocyte counts are typically seen only in primary EBV and CMV infection.” (2)

Laboratory testing may also include antibodies to EBV.  There are four different types of EBV antibodies: IgG antibodies for Early Antigen (EA-IgG), IgM antibodies to the viral capsid (VCA-IgM), IgG antibodies to the viral capsid (VCA-IgG), and IgG antibodies to the nuclear antigen (EBNA-IgG). These represent different phases of the immune system’s response to different parts of the virus itself.  Most labs provide a table to interpret the pattern of a patient’s results.  The following is from Labcorp:

EBV Interpretation Table (14)
Interpretation EBV-IgM EA(D)-IgG VCA-IgG EBNA-IgG
Key — Antibody present: + Antibody absent: −
EBV seronegative
Early phase +
Acute primary infection + ± +
Convalescence/past infection ± + +
Reactivated infection ± + + +

If all these antibody tests are negative, then it means the patient has never been exposed to EBV.  A positive titer for VCA-IgM indicates a primary EBV infection because the IgM antibodies are the first to appear and the first to disappear, typically within 3 months after infection. (2)  VCA-IgM antibodies can also reappear in a reactivated infection, but are not always present.  The EA-IgG and VCA-IgG antibodies develop after the IgM antibodies and there can be a time of overlap between the presences of these two types of antibodies.  The EBNA-IgG antibodies are the last to appear and VCA-IgG and EBNA-IgG persist for life.

According to the Merck Manual, “over 90% of adults are seropositive for EBV.” (2) This means that 90% of adults in the general population have been exposed to EBV and will show positives for past infection.  This is a very different pattern than that of patients with active infection.  Additionally, while the lab table indicates that the EA-IgG is positive for a reactivated infection, Dr. Oethinger , the director of microbiology at Providence Laboratory, indicated in personal communication that “the EA doesn’t need to be positive again during reactivation.” (15)  This means that the pattern between past and reactivated infections can be difficult to differentiate and individual patients must be evaluated based on symptoms as well as potential risks for future issues.

Treatment

Treatment of EBV needs to be assessed based on a patient’s current symptoms, test results, and concerns for possible development of future conditions linked to EBV.  Because I see many patients with autoimmune conditions, I am very concerned about the developing body of research linking EBV as a potential causative factor for many common autoimmune diseases.

Autoimmune diseases occur due to a combination of many different genetic and environmental factors.  Some factors, such as our genes, we cannot change.  There may be other factors medicine hasn’t identified yet.  Since these are areas we cannot treat, I look to those known environmental factors that are significant risk factors.   By reducing their impact, we can hopefully prevent future disease or reduce disease activity for those patients already diagnosed with autoimmune conditions.

Western medicine has no options for treatment of EBV infections except supportive care and corticosteroids possibly for severe disease. (2)  The anti-virals that are effective for other herpes family viruses (especially acyclovir) do not appear effective against EBV.  Studies have shown that acyclovir reduces shedding of EBV in saliva, but it does not change any single symptom or course of disease and viral titers returned to pre-treatment levels one to three weeks after cessation of therapy. (16, 17, 18) These are older studies, but as of February 2016, the Merck Manual still states “there is no convincing evidence to warrant (acyclovir’s) clinical use” for EBV infection. (2)  The Merck Manual does list two other medications as showing possible activity against EBV: cidofovir and foscarnet.  However, both of these medications are only given IV and are limited by significant kidney toxicity. (2)  Therefore, they would be reserved for the most severe cases.

Naturopathic medicine has many options for treating EBV both in terms of general anti-virals and options specifically designed for EBV.  Levels of immune-essential nutrients, such as vitamin A, vitamin D and zinc, can be optimized. Monolaurin is a byproduct of coconut oil and is commonly used as a general anti-viral.  Lysine, which is often used to treat herpes simplex outbreaks, can also be used for EBV, as can colostrum for patients who do not have issues with dairy.  There are numerous herbs, including olive leaf, garlic, goldenseal, Echinacea, and grape seed, and mushrooms, including cordyceps, turkey tail, shiitake, and lion’s mane, that can be used individually or in combination formulas.  Gemmotherapy preparations of several herbs are designed specifically to treat intra-cellular viruses, and essential oils can be added to herbal combinations.   Treatments can also include supporting the T-regulatory cells of the immune system, including probiotics, fish oil, vitamin D, and glutathione.

When using any of these therapies, it is important to start with low doses and increase slowly to patient’s tolerance.  Many people discuss “die-off” reactions with Lyme disease or candida overgrowth, and the same may be said for EBV infections.  As such, a complete plan would also include supports for detoxification and elimination, and would balance and rotate any anti-viral therapies.

Because these anti-virals are generally safe and well-tolerated, and the impacts of autoimmune disease can be devastating, this is one situation where I personally err on the side of treatment, especially in cases where patients have very high antibody levels.  My hope is that we can provide safe and relatively inexpensive treatment that could prevent a future autoimmune condition by treating a potential cause before symptoms arise.

Sources

(1) https://www.merckmanuals.com/professional/infectious-diseases/herpesviruses/overview-of-herpesvirus-infections

(2) https://www.merckmanuals.com/professional/infectious-diseases/herpesviruses/infectious-mononucleosis

(3) https://www.cdc.gov/epstein-barr/about-ebv.html

(4) Epstein-Barr virus-specific adoptive immunotherapy for progressive multiple sclerosis (https://www.ncbi.nlm.nih.gov/pubmed/24493474)

(5) Epstein-Barr virus in multiple sclerosis. (https://www.ncbi.nlm.nih.gov/pubmed/25162741)

(6) Multiple sclerosis and environmental factors: the role of vitamin D, parasites, and Epstein-Barr virus infection. (https://www.ncbi.nlm.nih.gov/pubmed/26046559)

(7) Epstein-Barr virus in systemic autoimmune diseases (https://www.ncbi.nlm.nih.gov/pubmed/24062777)

(8) Epstein-Barr virus and its association with rheumatoid arthritis and oral lichen planus. (https://www.ncbi.nlm.nih.gov/pubmed/26980953)

(9) Connective tissue diseases: Epstein-Barr virus in Sjögren’s syndrome salivary glands drives local autoimmunity. (https://www.ncbi.nlm.nih.gov/pubmed/24934188)

(10) The role of Epstein-Barr virus infection in the development of autoimmune thyroid diseases. (https://www.ncbi.nlm.nih.gov/pubmed/25931043)

(11) Epstein-barr virus as a trigger of autoimmune liver diseases. (https://www.ncbi.nlm.nih.gov/pubmed/22693505)

(12) Possible autoimmune hepatitis induced after chronic active Epstein-Barr virus infection. ( https://www.ncbi.nlm.nih.gov/pubmed/26183510)

(13) The immunology of Epstein-Barr virus-induced disease. (https://www.ncbi.nlm.nih.gov/pubmed/25706097)

(14) https://www.labcorp.com/test-menu/24771/epstein-barr-virus-ebv-acute-infection-antibodies-profile

(15) personal communication, Dr. Kimberly Hindman and Dr. Oethinger

(16) Acyclovir treatment in primary Epstein-Barr virus infection. A double-blind placebo-controlled study. (https://www.ncbi.nlm.nih.gov/pubmed/3006226)

(17) Acyclovir and Epstein-Barr virus infection. (https://www.ncbi.nlm.nih.gov/pubmed/6313591)

(18) Acyclovir treatment in infectious mononucleosis: a clinical and virological study. (https://www.ncbi.nlm.nih.gov/pubmed/3036715)

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