Infectious mononucleosis (IM) is an acute infectious disease caused by the Epstein-Barr virus (EBV). The clinical presentation is characterized by fever, pharyngitis, hepatosplenomegaly, lymphadenopathy, and an increased number of lymphocytes in the peripheral blood, including the presence of atypical lymphocytes. The diverse symptoms and signs, along with the incidence of atypical cases, can pose challenges for diagnosis and treatment.
Pathogen
The virus was first identified by Epstein and Barr in 1964 in tumor tissues from African children with Burkitt lymphoma. In 1968, Henle and colleagues identified EBV as the causative agent of this disease. EBV is a lymphotropic DNA virus in the herpesvirus family with characteristics of latency and transformation.
EBV contains five antigenic components, each capable of inducing specific antibodies:
Viral Capsid Antigen (VCA)
This induces both IgM and IgG antibodies. VCA-IgM antibodies appear early in infection and disappear after 1–2 months, indicating a recent EBV infection. VCA-IgG antibodies appear slightly later; low-affinity VCA-IgG antibodies can be detected in nearly all patients within the first month of a primary EBV infection. These gradually develop into high-affinity VCA-IgG antibodies that persist for years or even a lifetime. VCA-IgG positivity cannot differentiate between recent and past infections, which requires antibody affinity testing.
Early Antigen (EA)
This antigen is formed in the early proliferative stages of EBV. Its EA-D component is a marker of active EBV proliferation. EA-IgG antibodies peak 3–4 weeks after symptom onset and persist for 3–6 months.
Nuclear Antigen (EBNA)
EBNA-IgG antibodies emerge 3–4 weeks after symptom onset and persist for life, serving as a marker of past EBV infection.
Lymphocyte Determinant Membrane Antigen (LYDMA)
B cells with LYDMA are the target cells of cytotoxic T (Tc) cells. LYDMA antibodies are complement-fixing antibodies that appear and persist for time frames similar to EBNA-IgG antibodies, also marking past infections.
Membrane Antigen (MA)
This neutralizing antigen induces corresponding neutralizing antibodies with a temporal appearance and persistence similar to EBNA-IgG.
Epidemiology
Humans are broadly susceptible to EBV infection, with both symptomatic and asymptomatic individuals serving as sources of transmission. The virus is abundant in the salivary glands and saliva, with continuous or intermittent viral shedding lasting weeks, months, or even years. Transmission primarily occurs through contact with EBV-infected saliva, though blood transfusion is another rare route. The disease is most commonly observed among children and adolescents. Children under 6 years of age often exhibit silent or mild infections, while individuals over 15 years of age are more likely to develop typical symptoms.
Pathogenesis
After entering the oral cavity, EBV primarily infects cells such as pharyngeal epithelial cells, B lymphocytes, T lymphocytes, and NK cells, all of which express the EBV receptor CD21. The virus proliferates in pharyngeal epithelial cells, damaging these cells and leading to tonsillitis, pharyngitis, and local lymphadenopathy.
EBV can also replicate in the epithelial cells of the parotid and other salivary glands, resulting in prolonged or intermittent viral shedding into saliva. The virus then enters the bloodstream, disseminating via viremia or infected B lymphocytes and eventually involving the systemic lymphatic system. Alterations in the surface antigens of infected B lymphocytes trigger a robust immune response from T lymphocytes, transforming them into cytotoxic T cells (primarily CD8+ T cells, or cytotoxic T lymphocytes, CTLs). CTLs play a key role in immune-mediated pathological damage: they attack EBV-infected B lymphocytes but can also affect various tissues and organs, giving rise to clinical manifestations. Many atypical lymphocytes circulating in the blood—the so-called "abnormal lymphocytes"—are activated cytotoxic T cells.
Additional mechanisms of pathogenesis include interactions between B and T lymphocytes, immune complex deposition, and direct cellular damage by the virus. Cytokines produced by activated T lymphocytes may also contribute to disease progression, though the exact mechanism remains unclear. Infants and young children rarely develop typical presentations, likely due to an inability to mount an adequate immune response against EBV.
Pathology
Benign lymphoproliferation is the fundamental pathological feature of infectious mononucleosis. Histopathological findings reveal non-suppurative lymphadenopathy with pronounced proliferation of lymphocytes and mononuclear phagocytic cells. Involvement of vital organs such as the liver, heart, kidneys, adrenal glands, lungs, skin, and the central nervous system is characterized by infiltration of lymphocytes, monocytes, and atypical lymphocytes, as well as localized necrotic lesions.
The spleen is often engorged with atypical lymphocytes and exhibits edema, making it fragile, prone to hemorrhage, and at risk of rupture.
Clinical Manifestations
The incubation period is 5 to 15 days. The onset can be either abrupt or gradual, and symptoms are diverse. Most patients experience prodromal symptoms such as fatigue, headache, chills, nasal congestion, nausea, loss of appetite, and mild diarrhea. The severity of symptoms varies, and younger children tend to have less typical presentations. The typical manifestations during the active phase of the disease are as follows:
Fever
Fever is a common feature, with body temperatures ranging from 38°C to 40°C and no fixed fever pattern. The febrile period usually lasts 1 to 2 weeks but may last for several months in rare cases. Toxic symptoms are often mild.
Pharyngitis
The majority of pediatric patients exhibit congestion and swelling of the pharynx, tonsils, and uvula, sometimes accompanied by petechiae and throat pain. A white exudate or pseudomembrane may be observed on the surface of the tonsils in some cases. Severe pharyngeal swelling may cause difficulty in breathing or swallowing.
Lymphadenopathy
Generalized lymphadenopathy may occur, typically appearing during the first week of illness. It is most commonly observed in the cervical region. Enlargement of the epitrochlear (elbow) lymph nodes strongly suggests the possibility of this disease. The diameter of the enlarged lymph nodes is rarely greater than 3 cm, and they are moderately firm, non-tender, and not matted. Mesenteric lymphadenopathy may lead to abdominal pain. Lymphadenopathy often resolves within weeks after the fever subsides but may persist for months.
Hepatomegaly and Splenomegaly
Hepatomegaly is observed in approximately 20% to 62% of cases, usually with the liver palpable less than 2 cm below the costal margin. Abnormal liver function tests and upper gastrointestinal symptoms associated with acute hepatitis may occur, and mild jaundice may be observed in some cases. Splenomegaly occurs in about half of patients, occasionally accompanied by tenderness and pain. Rarely, splenic rupture may occur.
Rash
Some patients develop polymorphic rashes during the course of the disease, such as papules, maculopapular rashes, urticarial rashes, scarlatiniform rashes, or petechial rashes. Rashes are mostly localized to the trunk, typically appear around 4 to 6 days after onset, and resolve within about a week. Resolution of the rash occurs without peeling or pigmentation.
The course of the disease generally lasts 2 to 3 weeks, though it can extend to several months in some cases. Recurrence is rare and tends to be brief and mild. Infections in infants and young children are often asymptomatic or atypical, though EBV-specific antibodies may still be detected.
Complications
Severe cases may be complicated by neurological conditions such as Guillain-Barré syndrome, meningoencephalitis, or peripheral neuritis. During the acute phase, pericarditis, myocarditis, or EBV-related hemophagocytic syndrome may occur. Around 30% of patients develop secondary bacterial infections in the throat. Other rare complications include interstitial pneumonia, gastrointestinal bleeding, nephritis, autoimmune hemolytic anemia, aplastic anemia, agranulocytosis, and thrombocytopenia. Splenic rupture, although uncommon, is a serious complication that can be triggered by minor trauma.
Laboratory Tests
Complete Blood Count
Changes in the peripheral blood are a significant feature of the disease. Early in the illness, the total white blood cell count may be normal or slightly decreased, later increasing to >10×109/L, with some cases reaching 30–50×109/L. Early stages show neutrophilia, but lymphocytosis of over 60% develops later. Atypical lymphocytes appear, and their percentage exceeding 10% or an absolute count greater than 1.0×109/L is diagnostic. Some cases show reductions in hemoglobin and platelet counts.
Heterophile Agglutination Test (HAT)
Within the first week of illness, serum IgM heterophile antibodies appear and can agglutinate sheep or horse red blood cells, with a positive rate of 80% to 90%. An agglutination titer of ≥1:64 that remains positive after absorption with guinea pig kidney extract is diagnostic. These antibodies persist for 2 to 5 months. Children under 5 years of age often test negative.
EBV-Specific Antibody Testing
Indirect immunofluorescence and enzyme-linked immunoassays can detect VCA-IgM, low-affinity VCA-IgG, and EA-IgG in the serum. VCA-IgM positivity indicates recent EBV infection. Low-affinity VCA-IgG antibodies signify acute primary infection. Transient increases in EA-IgG levels suggest recent infection or active EBV replication. All of these markers have diagnostic significance.
EBV-DNA Detection
RT-PCR can rapidly, sensitively, and specifically detect high concentrations of EBV-DNA in serum. The presence of EBV-DNA indicates viremia.
Other Tests
Some patients may show elevated myocardial enzyme levels, abnormal liver function, renal impairment, or changes in T lymphocyte subsets, including a reduction or inversion of the CD4/CD8 ratio.
Diagnosis and Differential Diagnosis
Clinical diagnosis can be established based on epidemiological factors, typical clinical features (such as fever, sore throat, hepatosplenomegaly, and lymphadenopathy), and laboratory findings, including atypical lymphocytes exceeding 10% in peripheral blood, a positive heterophile agglutination test, positive EBV-specific antibodies (VCA-IgM, low-affinity VCA-IgG, and EA-IgG), and positive EBV-DNA detection. In particular, a positive VCA-IgM, and/or positive low-affinity VCA-IgG, and/or a fourfold or greater increase in VCA-IgG titers between paired acute and convalescent sera provide the most specific and valuable serological evidence for the diagnosis of acute EBV infection. A positive result confirms the diagnosis.
Differentiation is needed from other infections that cause lymphocytosis and monocytosis, such as cytomegalovirus, adenovirus, Mycoplasma pneumoniae, hepatitis A virus, and rubella virus infections. Misdiagnosis of EBV infectious mononucleosis as cytomegalovirus infection is the most common differential issue.
Treatment
No specific treatment is available, and management relies primarily on symptomatic care. Patients with splenomegaly should refrain from activities involving abdominal contact for 2 to 3 weeks to minimize the risk of splenic rupture, which can occur even with minor abdominal trauma. Antibiotics are ineffective for this disease and should only be used if secondary bacterial infections occur. Antiviral therapy, including drugs such as acyclovir, ganciclovir, and valacyclovir, is an option, though its effectiveness remains controversial.
Intravenous immunoglobulin can improve clinical symptoms and shorten the disease course, especially when administered early. Short courses of corticosteroids may significantly alleviate symptoms in severe cases. Splenic rupture requires immediate blood transfusion and surgical intervention. Treatment of EBV-associated hemophagocytic syndrome should follow relevant clinical guidelines.
Prevention
In addition to infectious mononucleosis, EBV infection is associated with several malignant conditions, including nasopharyngeal carcinoma and Hodgkin lymphoma. As a result, efforts are underway to develop EBV vaccines. These vaccines aim to not only prevent infectious mononucleosis but also provide immunoprevention for high-risk populations, such as children at risk for EBV-associated malignant lymphoma, nasopharyngeal carcinoma, primary immunodeficiencies, AIDS, and transplant recipients.
Prognosis
Infectious mononucleosis is a self-limiting disease with a generally favorable prognosis. The natural disease course typically lasts about 2 to 4 weeks, though recovery may be prolonged in some cases, taking weeks to months. The mortality rate is approximately 1% to 2%, primarily due to severe complications.