What is the pathophysiology, symptoms, and treatment of infectious mononucleosis (mono) caused by the Epstein-Barr virus (EBV) in adolescents and young adults?

Infectious Mononucleosis: Pathophysiology, Clinical Presentation, and Management

Pathophysiology and Disease Process

Infectious mononucleosis (mono) is caused primarily by Epstein-Barr virus (EBV), a ubiquitous herpesvirus that infects B-lymphocytes and has the ability to transform and immortalize these cells, leading to their proliferation. 1, 2

Viral Transmission and Epidemiology

• EBV is transmitted primarily through saliva, earning its reputation as the "kissing disease," though transmission via blood and droplets also occurs 3, 4
• At least 90% of adults worldwide are seropositive for EBV, with 40-90% seroprevalence by adolescence depending on socioeconomic status 5, 4
• The virus most commonly causes symptomatic disease in adolescents and young adults aged 15-24 years 3, 2
• Primary EBV infection in children under 10 years is usually asymptomatic or shows nonspecific symptoms 4

Viral Mechanism

• EBV's oncogenic potential relates to its ability to transform and immortalize B-lymphocytes, which can lead to uncontrolled proliferation particularly in immunodeficient individuals 5
• The incubation period ranges from 4-7 weeks before symptoms appear 4

Clinical Symptoms and Presentation

The classic triad of infectious mononucleosis consists of fever, tonsillar pharyngitis, and cervical lymphadenopathy, though presentations vary among patients. 3, 6

Primary Symptoms

• Sore throat and tonsillar pharyngitis - often the first presenting symptom 3, 6
• Fever - typically mild to moderate 3, 4
• Cervical lymph node enlargement - swollen lymph nodes in the neck area 3, 2
• Profound fatigue - tends to resolve within three months but can be the most debilitating symptom 3

Additional Clinical Features

• Periorbital and/or palpebral edema - typically bilateral, occurs in one-third of patients 3
• Splenomegaly - occurs in approximately 50% of cases 3
• Hepatomegaly - occurs in approximately 10% of cases, often with hepatitis 3, 4
• Skin rash - usually widely scattered, erythematous, and maculopapular, occurs in 10-45% of cases 3

Clinical Presentation Patterns

The presentations tend to fit into three clinical forms: pharyngeal, glandular, or febrile, which helps anticipate the clinical course and complications 6

Laboratory Findings

• Peripheral blood leukocytosis with lymphocytes comprising at least 50% of the white blood cell differential count 3
• Atypical lymphocytes constituting more than 10% of the total lymphocyte count 3
• Abnormal liver chemistries in 90% of patients 6

Diagnosis

The monospot test (heterophile antibody test) is the most widely used method for diagnosing infectious mononucleosis, but EBV-specific antibody testing is recommended when the monospot is negative in patients with mononucleosis-like illness. 3, 6

Diagnostic Approach

• Heterophile antibody testing (monospot) - can be conveniently performed in office laboratories and is the classic test for IM 3, 6
• EBV-specific serologic testing - when confirmation is required in patients with negative monospot test, testing for antibodies to viral capsid antigens (VCA) is recommended 3

Serologic Patterns for Staging EBV Infection

• Primary acute infection: Positive VCA IgM, positive or negative VCA IgG, negative EBNA 7
• Past infection: EBV IgG >8.0 without accompanying IgM antibodies indicates past infection rather than acute infection 7
• VCA IgM indicates recent or acute infection when positive 7

Important Diagnostic Considerations

• Other causes of mononucleosis syndrome: Cytomegalovirus (CMV), Toxoplasma gondii, and acute HIV infection can also produce mononucleosis syndromes and should be considered 1, 8
• Approximately 10% of those with IM will not be acutely infected with EBV, with many cases attributed to CMV infection 8

Treatment and Management

Treatment of infectious mononucleosis is mainly supportive, as the disease is generally benign and self-limited, with most patients having an uneventful recovery. 3, 4

Supportive Care

• Activity modification: Reduction of activity and bed rest as tolerated are recommended 3
• Adequate analgesia for symptom relief 6
• Avoidance of contact sports or strenuous exercise for 8 weeks or while splenomegaly is still present to prevent splenic rupture 3

Pharmacologic Interventions

• Corticosteroids are indicated for patients with upper airway obstruction and may be helpful in patients with neurologic, hematologic, or cardiac complications 6
• Acyclovir may prove useful, but further studies are needed before its use can be routinely recommended 6
• A generally effective specific therapy does not currently exist 4

Duration and Recovery

• Symptoms usually subside after a few weeks, though protracted courses and clinically active infection can occur 4
• Fatigue may be profound but tends to resolve within three months 3

Complications and Red Flags

Life-Threatening Complications

• Spontaneous splenic rupture occurs in 0.1-0.5% of patients and is potentially life-threatening, making it the most feared complication 3
• Upper airway obstruction requiring corticosteroid intervention 6

Serious Complications Requiring Further Evaluation

• Persistent fever beyond 10 days after EBV diagnosis is not typical of uncomplicated primary EBV infection and warrants further investigation for chronic active EBV infection (CAEBV) or hemophagocytic lymphohistiocytosis (HLH) 9
• Chronic Active EBV Infection (CAEBV) is characterized by persistent or recurrent infectious mononucleosis-like symptoms lasting weeks to months, including persistent fever, lymphadenopathy, and/or hepatosplenomegaly 5, 9
• Hemophagocytic Lymphohistiocytosis (HLH) is an EBV-triggered hyperinflammatory syndrome with persistent fever, cytopenias, and extremely elevated ferritin levels (>1000 ng/mL) 9

Additional Complications

• Neurologic abnormalities - a wide variety can occur 6
• Thrombocytopenic purpura 6
• Infectious mononucleosis is a risk factor for chronic fatigue syndrome 3

Diagnostic Workup for Persistent Symptoms

• Quantitative EBV PCR with viral loads >10^2.5 copies/μg DNA in peripheral blood mononuclear cells suggests CAEBV 5, 9
• Cytokine analysis showing elevated inflammatory cytokines may indicate HLH or CAEBV 9
• Bone marrow examination may be necessary if HLH is suspected to look for hemophagocytosis 9

Critical Clinical Pitfalls to Avoid

• Assuming all EBV infections are self-limiting can lead to delayed diagnosis of CAEBV or HLH, both of which require aggressive management and have poor prognosis if untreated 9
• Overlooking HLH can be life-threatening, requiring prompt diagnosis and treatment 9
• Failing to advise patients about activity restrictions increases the risk of splenic rupture 3
• Not considering alternative diagnoses such as CMV, toxoplasmosis, or acute HIV when heterophile antibodies are negative 1, 8