Epstein-Barr virus

The Epstein-Barr virus or EBV or Human Herpesvirus 4 or HHV-4 is a herpesvirus. It is the most common cause of infectious mononucleosis or "glandular fever," and infects 90% of adults worldwide. It has been implicated in numerous immune diseases and chronic illnesses, including chronic fatigue syndrome, multiple sclerosis, myasthenia gravis, and systemic lupus erythematosus. It is known to turn on "risk genes" for autoimmune disease in the cells it infects.

Initial infection
Symptoms of EBV infection include:
 * fatigue
 * fever
 * rash
 * inflamed throat
 * swollen lymph nodes
 * enlarged spleen
 * swollen liver

Age of infection
Most people acquire EBV in early childhood. Typically, young children who acquire EBV are either not symptomatic or have mild symptoms that are hard to distinguish from a cold or other other mild, childhood illnesses.

In adolescents and young adults, EBV can cause infectious mononucleosis (IM), also known as glandular fever. IM is characterized by fever, sore throat, swollen lymph nodes, body aches, and fatigue. It generally resolves with rest and only rarely causes serious complications. It typically occurs in people who have not been exposed to EBV in early childhood, and in comparison, is more severe than infection in childhood (i.e., it can last for months).

Following initial infection, EBV can reactivate and has been shown to have many connections with various chronic illnesses. Relative to initial infections, reactivated EBV is much more severe.

Transmission
EBV is transmitted through bodily fluids, most commonly through saliva. The first time a person is infected with EBV, the person is contagious for weeks (even when not displaying symptoms). The virus then transitions to the latent or inactive form, and stays in the body. If the virus reactivates, the person will be contagious again.

Diagnosis
EBV infection is confirmed with blood tests that detect presence of antibodies. Nine out of ten adults have these antibodies, indicating that they have a current or past EBV infection.

Anti-VCA (Viral capsid antigen) IgG and EBV nuclear antigen (EBNA) IgG antibodies persist throughout a person's life. Thus, positive results merely indicate a current or past infection. A current EBV infection is diagnosed based on the presence of Anti-VCA IgM and Anti-EA (Early Antigen) IgG. VCA IgM appears early in EBV infection and usually disappears within four to six weeks. Positive VCA IgM suggests current active acute EBV infection. EA IgG appears in the acute phase of illness and generally falls to undetectable levels after three to six months. Positive EA IgG can suggest current active EBV infection or EBV re-activation.

Latency
In healthy adults, the virus remains latent for life in memory B cells. It is estimated that 1 in every one hundred thousand to one million circulating B cells carry EBV. In healthy hosts, EBV populations are kept in check by CD4+ and CD8+ T-cell responses.

The equilibrium can be disrupted in individuals with compromised immune systems such as patients with AIDS or transplant patients taking immune system suppressing drugs. It has been observed that these patients are more susceptible to EBV-related cancers, such as certain lymphomas and carcinomas. In immunocompromised patients, EBV can induce lymphoproliferation, lymphoma, and hemophagocytic lymphohistiocytosis (HLH).

Natural killer T cells
It is thought that natural killer T cells (NKT) play a pivotal role in the control of EBV-infected B cells through their recognition of CD1d expressing cells.

Neuronal infection
A 2015 study demonstrated that human neuronal cells could be directly and actively infected with EBV and another herpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV).

Neuronal cells were infected with EBV or KSHV viruses which had been combined with a fluorescent protein so that the infection could be observed. The infection was seen to produce new virus cells (productive) and spread efficiently. Significantly, it not only infected surrounding neuronal cells but also nearby peripheral blood mononuclear cells.

EBV is known to be linked to many neuronal diseases but this is the first evidence of how this may occur. The researchers note that this research supports the presence of EBV in neuronal diseases, but does not indicate why this is so.

In human disease
Epstein-Barr virus has been associated with a wide number of immune diseases including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Chronic fatigue syndrome, and myasthenia gravis. EBV was recently discovered to turn on "risk genes" for autoimmune disease in the cells it infects. EBNA2, a protein produced by EBV-infected cells, and its related transcription factors activate half the human genes known to be associated with the risk for lupus as well as genes associated with several other autoimmune diseases including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis and celiac disease. EBV activation can thus increase the risk of developing these diseases.

Chronic fatigue syndrome
A prospective study of 250 primary care patients revealed a higher prevalence of chronic fatigue syndrome after infectious mononucleosis (glandular fever) when compared to an ordinary upper respiratory tract infection. Anti-early antigen titers to EBV were elevated in CFS patients and associated with worse symptoms. A 2006 Australian prospective study found that 12% of subjects infected by EBV met the criteria for chronic fatigue syndrome six months after their infection, and 9% still had CFS 12 months after infection. (The same rate held true for Ross River virus and Q fever). In another study sample, 110 of 178 patients with increased antibodies against EBV had a diagnosis of CFS.

Long COVID
Long COVID may be associated herpesvirus reactivation such as EBV.

Multiple sclerosis
Infection later in life, high serum titers against EBV, and mononucleosis have all been associated with an increased risk of multiple sclerosis. MS relapses are correlated with EBV reactivation.

Several studies by Alberto Ascherio, MD, DrPH, and his team at the Harvard School of Public Health have suggested that EBV is involved in multiple sclerosis, specifically in people with a certain immune-related gene and high levels of antibodies to EBV in their blood.

Systemic lupus erythematosus
In a study of young patients with lupus, 99% had EBV as compared to 70% of healthy controls. Another study found that patients with systemic lupus erythematosus had a roughly 40-fold increase in EBV viral loads compared with controls, likely stemming from altered t cell responses against EBV.

Myasthenia gravis
Myasthenia gravis is an autoimmune disease which has been associated with a large number of different viruses, particularly EBV, HPV, and polioviruses. In several studies EBV infection of the thymus has been found in myasthenia gravis patients, but not all studies have found this. B cells from myasthenia gravis patients stimulated in vitro by Epstein-Barr virus produced acetylcholine autoantibodies. While EBV infection of the thymus has been posited as a causative agent for the production of acetylcholine receptor autoantibodies in myasthenia gravis. , there is only limited evidence supporting EBV or other viruses as a cause of myasthenia gravis.

Gastrointestinal disease
One study of EBV in patients with gastritis, Crohn's disease, and ulcerative colitis and normal controls found essentially undetectable levels of EBV in normal gastric mucosa. However, EBV was detected in 46% of gastritis lesions, 44% of normal colonic mucosa, 55% of Crohn’s disease, and 64% of ulcerative colitis samples.

Lyme disease
Several herpesviruses including Epstein-Barr virus may cause false positives on Lyme disease tests.

XMEN disease
A 2014 study found chronic Epstein-Barr infection was linked to a magnesium transporter MAGT mutation. Dysfunction in this transporter also resulted in decreased NK cell function, and neoplasia (sometimes-cancerous growths).

This disorder, termed "XMEN" (for X-linked, EBV, and neoplasia) was identified as a recessive, X-linked disorder that would therefore be many times more common in men.

Since chronic EBV infection has been associated with chronic fatigue syndrome, this error in magnesium transport may be worth considering in male patients, especially with slow onset and history of childhood infection. However, in this disorder, EBV would be seen as an indicator of the illness rather than the cause.

Vitamin D
Some recent research is finding links between EBV and Vitamin D.

An EBV protein, EBNA-3, has an affinity for the vitamin D receptor (VDR) and may actually block the activation of VDR-dependent genes by Vitamin D.

Vitamin D receptor may be required for the normal development of natural killer T cells that react to cells expressing CD1d, as in cells infected by EBV. VDR is expressed on B cells infected with EBV, and bioactive Vitamin D3 alters T cells to be less detrimental to the immune response.

As low Vitamin D is also a risk factor for MS, some studies have attempt to find a link between low Vitamin D status, EBV, and MS. One study of healthy individuals found no link between EBV load and Vitamin D status. However, over half the subjects were Vitamin D deficient and none had optimal levels (i.e., above 100 nmol/l).

Treatment
There is no specific treatment for EBV, only treatment of symptoms, such as taking over-the-counter medications for pain and fever. EBV is thought to persistent harmlessly in immunocompetent individuals, but in those with compromised immune systems it has been associated with certain cancers and possibly autoimmune disease.

Antivirals
Several antivirals are active against EBV including valganciclovir, valacyclovir, acyclovir , and spironolactone.

Acyclovir, an antiviral drug which inhibits (but does not destroy) herpesviruses, was shown to also inhibit the virus production. This suggests that EBV replicates via lytic replication.

A theoretical immunotherapy treatment proposes that inducing CD1d expression on EBV-infected B cells could prompt effective immune suppression of EBV by natural killer T cells.

Rituximab
Rituximab may be effective in completely eliminating EBV infection from the peripheral blood. A study of seventeen patients with low-grade B cell lymphoma found that after three cycles of rituximab, the virus had been completely eliminated from the peripheral blood in all but one patient.

Herbs and nutraceuticals
Though not tested in clinical trials, licorice derivatives quercetin and isoliquiritigenin inhibit EBV in cell cultures. Vitamin C and Vitamin D3 might also decrease duration and severity of the symptoms of EBV infection.

Vaccine
A vaccine for the prevention of Epstein-Barr virus is being explored.

Notable studies

 * 1996, MMPI profiles of patients with chronic fatigue syndrome - (Abstract)
 * 1998, Incidence, risk and prognosis of acute and chronic fatigue syndromes and psychiatric disorders after glandular fever - (Abstract)
 * 2006, Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study - (Full text)
 * 2019, EBV-requisitioning physicians' guess on fatigue state 6 months after acute EBV infection - (Abstract)
 * 2019, Predictors of chronic fatigue in adolescents six months after acute Epstein-Barr virus infection: A prospective cohort study - (Abstract)
 * 2019, Lifestyle factors during acute Epstein-Barr virus infection in adolescents predict physical activity six months later - (Abstract)
 * 2019, Epstein-Barr Virus dUTPase Induces Neuroinflammatory Mediators: Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - (Full text)
 * 2019, Review article - Epstein-Barr virus induced gene-2 upregulation identifies a particular subtype of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis - (Full text)
 * 2019, Epstein-Barr virus (EBV) reactivation and therapeutic inhibitors - (Abstract)
 * 2020, Cytomegalovirus, Epstein-Barr Virus, and Human herpesvirus-6 Infections in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - (Abstract)
 * 2021, Epstein-Barr Virus and the Origin of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome - (Full text)
 * 2021, Lasting Immunological Imprint of Primary Epstein-Barr Virus Infection With Associations to Chronic Low-Grade Inflammation and Fatigue - (Full text)
 * 2021, Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation (Full text)
 * 2022, EBV/HHV-6A dUTPases contribute to myalgic encephalomyelitis/chronic fatigue syndrome pathophysiology by enhancing TFH cell differentiation and extrafollicular activities - (Full text)

Learn more

 * Antiviral agents for infectious mononucleosis (glandular fever) (2016) - Cochrane review
 * Study Provides Strongest Evidence Yet for the Role of Epstein-Barr Virus in Triggering Multiple Sclerosis (2022) - Multiple Sclerosis Society