Epstein-Barr Virus Infections, Including Infectious Mononucleosis¶
Chapter 199 | Harrison's 22e · Part 5 – Infectious Diseases: Viral (incl. HIV) · Chapter 199
Key Clinical Points¶
- EBV causes heterophile-positive infectious mononucleosis (IM) characterized by the triad of fever, sore throat, and lymphadenopathy.
- Atypical lymphocytosis (CD20+ B cells with irregular nuclei) is a hallmark hematologic finding in acute IM.
- Over 90% of adults worldwide show serologic evidence of EBV infection.
- Serological markers: IgM anti-VCA (acute), Heterophile (acute), IgG anti-VCA (ongoing/past), and EBNA (past infection).
- Splenomegaly occurs in approximately 50% of IM cases; splenectomy is contraindicated due to risk of EBV reactivation.
- Oral hairy leukoplakia is a clinical manifestation associated with EBV in immunocompromised patients (e.g., HIV-positive).
- EBV is linked to several malignancies, including Burkitt’s lymphoma, Hodgkin’s lymphoma, nasopharyngeal carcinoma, and gastric carcinoma.
- Acyclovir suppresses oropharyngeal shedding but does not eliminate latent infection in B cells.
- Differential diagnosis includes CMV (older age), HIV (rash/ulcers), and Lymphoma (fixed nodes).
- No licensed EBV vaccine exists; prevention relies on barrier precautions and blood screening.
1. DEFINITION & OVERVIEW¶
• Definition (Harrison's 22e): Epstein-Barr virus (EBV) is the cause of heterophile-positive infectious mononucleosis (IM), which is characterized by fever, sore throat, lymphadenopathy, and atypical lymphocytosis. EBV is also associated with several tumors, including nasopharyngeal and gastric carcinoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, T-cell and B-cell lymphoma, and smooth muscle tumors. • Classification: Member of the Herpesviridae family. • Pathogen Characteristics: Infects oropharyngeal epithelium and salivary glands; persists in memory B cells after acute infection. EBV is linked to multiple sclerosis epidemiologically.
2. EPIDEMIOLOGY¶
• Seroprevalence: >90% of adults worldwide have evidence of EBV infection. • Demographics: IM typically affects young adults (15-35 years). • Geographic Variation: IM is uncommon in lower socioeconomic regions where childhood infections are more prevalent; in high-hygiene settings, infection often occurs during adolescence or early adulthood. • Transmission Routes: → Saliva (e.g., kissing) → Blood transfusion → Organ transplantation → Vertical transmission
3. PATHOGENESIS¶
• Infection Route: Initial infection via salivary secretions → infects oropharyngeal epithelium and salivary glands. • Systemic Spread: Virus spreads through bloodstream to B cells in tonsillar crypts. • Latency: EBV establishes latency in memory B cells; viral proteins (EBNAs, LMPs) are expressed during latency. • Receptor Mechanism: → CD21 (CR2) is the primary EBV receptor on B cells → HLA class II serves as co-receptor • Pharmacology Note: Acyclovir suppresses oropharyngeal shedding but does not treat latent infection in B cells.
4. CLINICAL MANIFESTATIONS¶
• Classic IM Triad: Fever, pharyngitis, and lymphadenopathy. • Hematologic Findings: Atypical lymphocytosis (CD20+ B cells with irregular nuclei). • Organ Involvement: → Splenomegaly in 50% of cases → risk of splenic rupture → Hepatomegaly and mild transaminitis are common. • Constitutional Symptoms: Fatigue, malaise, weight loss. • Complications: Airway obstruction, hemophagocytic lymphohistiocytosis (HLH), encephalitis. • Cutaneous Manifestations: Maculopapular rash (Figure 199-1).
5. DIAGNOSTIC APPROACH¶
- Clinical Assessment: Diagnosis based on presence of fever (>3 days), pharyngitis, lymphadenopathy, and atypical lymphocytes.
- Monospot Test: Used for detection of heterophile antibodies.
- EBV Serology (Figure 199-4): → IgM anti-VCA: Marker for acute infection (early peak). → Heterophile: Peaks at ~1 month; used for diagnosis in acute phase. → IgG anti-VCA: Indicates past or ongoing infection; persists over time. → EBNA: Appears later; serves as a marker for past infection (not detectable in first few months of acute infection).
- Molecular Testing: PCR for EBV DNA in blood or CSF.
6. MANAGEMENT & TREATMENT¶
- Supportive Care: Provide rest, hydration, and analgesia.
- Corticosteroid Therapy: → Indication: Severe airway obstruction or hemophagocytic syndrome → Dosage: Prednisone 1-2 mg/kg/day.
- Antiviral Therapy: → Acyclovir: 800 mg PO TID x 2 weeks (for immunocompromised patients with active infection). → Valganciclovir: 15 mg/kg BID x 2 weeks (for severe cases).
- Surgical Note: Splenectomy is contraindicated in IM due to risk of EBV reactivation.
7. DIFFERENTIAL DIAGNOSIS¶
• Comparison of Infectious Etiologies (Table 199-2): → EBV infection: Fever (+), Adenopathy (+), Sore throat (+), Atypical lymphocytes (+). → HIV infection: Fever (+), Adenopathy (+), Sore throat (+), Atypical lymphocytes (±). Differences: Diffuse rash, oral/genital ulcers, aseptic meningitis. → HHV-6 infection: Fever (+), Adenopathy (+), Sore throat (+), Atypical lymphocytes (+). Difference: Older age at presentation. → Viral hepatitis: Fever (+), Adenopathy (±), Sore throat (-), Atypical lymphocytes (±). Difference: Higher aminotransferase levels. → Toxoplasmosis: Fever (+), Adenopathy (+), Sore throat (not specified), Atypical lymphocytes (less common). → Streptococcal pharyngitis: (Included in differential, but specific differences not listed in table). → Rubella: (Included in differential, but specific differences not listed in table). • Non-Infectious Etiologies: → Lymphoma: Fever (+), Adenopathy (+), Sore throat (+), Atypical lymphocytes (+). Difference: Fixed, nontender lymph nodes. → Drugs: (Included in differential).
8. ASSOCIATED CONDITIONS & PREVENTION¶
• Malignancies: Burkitt’s lymphoma, Hodgkin’s lymphoma, nasopharyngeal carcinoma, gastric carcinoma. • Immunodeficiency Syndromes: X-linked lymphoproliferative disorder (XLP). • Autoimmune Associations: Multiple sclerosis, systemic lupus erythematosus. • Oral Manifestations: Hairy leukoplakia in HIV patients (white, 'hairy' plaques on lateral tongue; Figure 199-3). • Vaccination & Prevention: → No licensed EBV vaccine available. → Prevention: Avoid close contact with infected individuals, use barrier precautions, and blood donor screening.
9. VACCINATION & PREVENTIVE MEASURES¶
• Varicella-zoster virus (VZV) vaccination guidelines (Table 198-1): → Indicated for immunocompromised children, pregnant women, and neonates with maternal chickenpox. → VZIG administration must occur within 96 hours of exposure.
VZIG Administration Criteria¶
• Exposure Scenarios: → Household: Residence in same household. → Playmate: Face-to-face indoor play. → Hospital: Same 2-4 bed room or adjacent beds in a large ward, face-to-face contact with an infectious staff member or patient, visit by a person deemed contagious. → Newborn: Maternal chickenpox ≤5 days before delivery or ≤48 h after delivery (not indicated if mother has zoster). • Candidate Groups for VZIG: → Immunocompromised susceptible children without a history of varicella or varicella immunization. → Susceptible pregnant women. → Neonates with maternal chickenpox within 5 days before or 48 h after delivery. → Hospitalized premature infant (≥28 weeks of gestation) whose mother lacks a reliable history of chickenpox or serologic evidence of protection against varicella. → Hospitalized premature infant (<28 weeks of gestation or ≤1000-g birth weight), regardless of maternal history of varicella or VZV serologic status.
10. CLINICAL DATA SUMMARY¶
• Symptom Prevalence (Table 199-1): → Fever: 93% (60-100%) → Sore throat: 75% (50-87%) → Splenomegaly: 51% (43-64%) → Rash: 10% (0-25%) → Headache: 38% (22-67%) → Chills: 10% (9-11%) → Palatal enanthem: 7% (3-13%)
Reference Tables¶
TABLE 198-1 Recommendations for VZIG Administration Exposure Criteria 1. Significant exposure to a person with…¶
Harrison's 22e, p.1508
| Exposure Criteria | |
|---|---|
| 1. Significant exposure to a person with chickenpox or zoster a. Household: residence in the same household b. Playmate: face-to-face indoor play c. Hospital Varicella: same 2- to 4-bed room or adjacent beds in a large ward, face-to- face contact with an infectious staff member or patient, visit by a person deemed contagious Zoster: intimate contact (e.g., touching or hugging) with a person deemed contagious d. Newborn infant: onset of varicella in the mother ≤5 days before delivery or ≤48 h after delivery; VZIG not indicated if the mother has zoster 2. Patient should receive VZIG as soon as possible but not >96 h after exposure. |
|
| Candidates (Provided They Have Significant Exposure) Include | |
| 1. Immunocompromised susceptible children without a history of varicella or varicella immunization 2. Susceptible pregnant women 3. Newborn infants whose mother had onset of chickenpox within 5 days before or within 48 h after delivery 4. Hospitalized premature infant (≥28 weeks of gestation) whose mother lacks a reliable history of chickenpox or serologic evidence of protection against varicella 5. Hospitalized premature infant (<28 weeks of gestation or ≤1000-g birth weight), regardless of maternal history of varicella or VZV serologic status |
|
| 199 | Epstein-Barr Virus Infections, Including Infectious Mononucleosis Jeffrey I. Cohen |
TABLE 199-1 Signs and Symptoms of Infectious Mononucleosis MANIFESTATION Symptoms Sore throat Malaise Headache…¶
Harrison's 22e, p.1509
| MANIFESTATION | MEDIAN PERCENTAGE OF PATIENTS (RANGE) |
|---|---|
| Symptoms | |
| Sore throat | 75 (50–87) |
| Headache | 38 (22–67) |
| Chills | 10 (9–11) |
| Signs | |
| Fever | 93 (60–100) |
| Splenomegaly | 51 (43–64) |
| Rash | 10 (0–25) |
| Palatal enanthem | 7 (3–13) |
TABLE 199-2 Differential Diagnosis of Infectious Mononucleosis¶
Harrison's 22e, p.1511
| SIGN OR SYMPTOM | |||||
|---|---|---|---|---|---|
| ETIOLOGY | FEVER | ADENOPATHY | SORE THROAT | ATYPICAL LYMPHOCYTES | DIFFERENCES FROM EBV MONONUCLEOSIS |
| EBV infection | + | + | + | + | — |
| + | ± | ± | + | ||
| HIV infection | + | + | + | ± | Diffuse rash, oral/genital ulcers, aseptic meningitis |
| + | + | ± | ± | ||
| HHV-6 infection | + | + | + | + | Older age at presentation |
| + | + | + | – | ||
| Viral hepatitis | + | ± | – | ± | Higher aminotransferase levels |
| + | + | ± | ± | ||
| Lymphoma | + | + | + | + | Fixed, nontender lymph nodes |
| + | + | – | ± |