Epstein-Barr Virus (EBV) Infectious Mononucleosis (Mono)

Updated: Apr 21, 2021
  • Author: Kartika Shetty, MD, FACP; Chief Editor: Michael Stuart Bronze, MD  more...
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Epstein-Barr virus (EBV), also known as human herpes virus 4, is a widely disseminated double stranded DNA herpesvirus. It is the causative agent of infectious mononucleosis ("mono" or "glandular fever").

Since the 1800s, infectious mononucleosis has been recognized as a clinical syndrome consisting of fever, pharyngitis, and adenopathy. The term glandular fever was first used in 1889 by German physicians and was termed Drüsenfieber. Infectious mononucleosis was first described by Sprunt and Evans in the Bulletin of the Johns Hopkins Hospital in 1920. [1]  They described the clinical characteristics of EBV infectious mononucleosis. At the time, their article was entitled "Mononuclear leukocytosis in reaction to acute infection (infectious mononucleosis)" because the causative organism, EBV, had yet to be described.



Epstein-Barr virus (EBV) is transmitted via intimate contact with body secretions, primarily oropharyngeal secretions and to a lesser degree through genital secretions. It infects the B cells in the oropharyngeal epithelium; after acute infection the virus has been detected in oro-pharyngeal secretions for up to 32 weeks [2]  and may persist for decades. On rare occasion, EBV is spread via blood transfusion and organ transplantation.

Epstein-Barr virus infection of B lymphocytes results in a humoral and cellular response to the virus. The humoral immune response directed against EBV structural proteins is the basis for the test used to diagnose EBV infectious mononucleosis, but the T-lymphocyte cellular response is critical in determining the clinical expression of EBV infection. Natural killer (NK) cells and predominantly CD8+ cytotoxic T cells control proliferating B lymphocytes infected with EBV.

Ineffective T-cell response may cause excessive and uncontrolled B-cell proliferation, resulting in B-lymphocyte malignancies (eg, B-cell lymphomas).

The immune response to EBV infection is fever, which occurs because of cytokine release consequent to B-lymphocyte invasion by EBV. Lymphocytosis observed in the reticuloendothelial system (RES) is caused by a proliferation of EBV-infected B lymphocytes and similar proliferation in the lymphatic tissue of the oropharynx causes pharyngitis.



Epstein-Barr Virus (EBV) is among the most prevalent human viruses in the world. [3]  It is estimated that 90% of the global population is seropositive for EBV, [4]  with developed countries bearing a comparatively lower burden of EBV seroprevalence. [5]  Residents of developed countries also experience primary EBV infection at a later age. [6]  In the United States, the EBV seroprevalence for children and adolescents between the ages of 6-19 is about 66.5%, with female, African-American, and Hispanic populations experiencing significantly higher rates of seropositivity. [5]  Significant seroprevalence differences exist by family income, with children in the lowest income quartile having 81.0% seroprevalence compared with 53.9% in the highest income quartile. [5]  In US institutions characterized by the presence of many young adults, such as universities and the armed forces, the annual incidence for infectious mononucleosis ranges from 11 to 48 cases per 1000 persons. [7]




Various complications related toEpstein-Barr virus (EBV), either directly or secondary to unregulated immune response, are described in the literature. Important conditions include the following:

Airway obstruction 


Renal complications

Nervous System complications


Chronic Active EBV (CAEBV)

Lymphoproliferative disorders 

Posttransplantation lymphoproliferative disorders (PTLD)

Splenic Rupture  - Splenomegaly is a common presentation among those with infectious mononucleosis, and although splenic rupture is rare, it can be life-threatening. Most spleen ruptures occur after even mild abdominal trauma and are more likely to occur between day 4 and 21 of the illness. Rest and restriction from weight-lifting and contact sports should be implemented at least for the first 4 weeks on onset of symptoms. These patients can present with non-specific abdominal pain, left upper quadrant pain that radiates to the left shoulder, acute drop in Hematocrit, or shock. [8, 9]  Some will require splenectomy and others will require supportive care which is the preferred treatment. [10]  

Airway obstruction - Obstruction of the upper airway due to massive lymphoid hyperplasia and mucosal edema is an uncommon but potentially fatal complication of infectious mononucelosis.

Fatigue - Patients with EBV infection who present clinically with infectious mononucleosis invariably experience accompanying fatigue. Fatigue may be profound initially but usually resolves gradually in 3 months. Some patients experience prolonged fatigue and, after initial recovery, enter a state of prolonged fatigue without the features of infectious mononucleosis.

Renal Complications -  Epstein-Barr virus is connected to a variety of renal syndromes, including interstitial nephritis, myositis-associated acute kidney injury, hemolytic uremic syndrome, and jaundice-associated nephropathy. [11]  Although rare, there are documented cases of fatalities resulting from the aforementioned diseases.

Nervous System Disorders- Central nervous system (CNS) mononucleosis is also responsible for increased morbidity in infectious mononucleosis.

A further source of morbidity in the context of this disease is research that points to a link between EBV and the development of multiple sclerosis (MS). Epstein-Barr virus seroprevalence is higher among people with MS, symptomatic EBV infection (IM) is more prevalent among people with MS and higher anti-EBV antibody titers are associated with an increased risk for MS. [12]  Epstein-Barr virus infection appears to be a necessary but not sufficient requirement for developing MS. Multiple sclerosis is overwhelmingly likely to be the result of multiple environmental risk modifiers.



Although primarily a disease of young adults, EBV infectious mononucleosis may occur from childhood to old age.