Infectious Mononucleosis Syndromes

Carla S. Wilson, MD, PhD

Key Facts

Terminology

IM is an acute illness
- Mainly due to EBV infection
- ˜ 20% of cases due to CMV or other viral infection

Clinical Issues

EBV: Clinical triad of sore throat, fever, and lymphadenopathy
CMV: Persistent fever often predominates
- Pharyngitis and tonsillitis are rare

Microscopic Pathology

Hallmark is peripheral blood findings
- Lymphocytes and monocytes are > 50% of leukocytes
- > 10% are atypical lymphocytes
- Marked lymphocyte heterogeneity
EBV infection
- Downey type II and III cells common
- Autoimmune hemolytic anemia, primarily anti-i antibodies
CMV infection
- Circulating infected endothelial cells in immunosuppressed individuals are diagnostic
Bone marrow evaluation usually not required
- Nonspecific reactive changes: Lymphocytosis, plasmacytosis, granulomatous infiltrates
- Transient bone marrow suppression
- CMV-infected cells may appear normal or have “owl’s eye” viral inclusions

Ancillary Tests

Immunohistochemistry or in situ hybridization for EBV or CMV are confirmatory

A prominent lymphocytic reaction is present in this peripheral blood smear from a 16-year-old female with infectious mononucleosis and EBV-positive serology.

The blood film from an adolescent male with infectious mononucleosis shows prominent red blood cell clumping. This is caused by cold agglutinin disease associated with EBV infection.

TERMINOLOGY

ETIOLOGY/PATHOGENESIS

Herpesvirus Family

Double-stranded DNA viruses
- Envelope derived from host cell membrane
- Symptomatic disease associated with lytic virus replication
- Latent infection after recovery from acute infection
EBV
- Gamma-1 herpes virus
- Infects B cells
  - Receptors are CD21, MHC class II
  - Majority of infected B cells are rapidly cleared from circulation in immunocompetent individuals
  - Elicits T-cell and early natural killer (NK) cell response
- Latency established in lymphoid cells or fibroblasts
  - EBV genome circularizes in nucleus of B lymphocytes and is replicated as an episome
  - Memory B cells remain quiescently infected and serve as reservoir for lifelong infection
CMV
- Beta herpes virus
- Infects epithelial cells, endothelial cells, neuronal cells, smooth muscle cells, fibroblasts, monocytes, macrophages, and T cells
  - Infects cells by endocytosis
  - Does not infect B cells
- Cell-mediated immunity plays primary role in controlling infection
- Individuals may develop primary or secondary infection
  - Primary infection occurs in seronegative individuals who were never previously infected
  - Secondary infection is activation of previously latent infection or reinfection by different CMV strain

CLINICAL ISSUES

Epidemiology

Incidence
- Clinically apparent IM
  - More common in populations with delayed primary EBV or CMV exposure
  - EBV-associated IM: 45.2 cases per 100,000 people per year in USA
  - May have primary EBV/CMV coinfection or mixed infection with other organism
- Clinically silent infection
  - Usually infants or children
  - Frequently negative for heterophile antibody
- CMV infection in immunosuppressed individuals
  - Most common viral opportunistic infection in AIDS; often multiple CMV strains
  - Reactivation of virus common in stem cell or solid organ transplant patients
  - Infection occurs 1-3 months after transplant if no prophylaxis, 4-8 months if failed prophylaxis treatment
  - CMV viremia seen in 30% of at-risk pediatric lung transplant patients
Age
- Older age suggests CMV rather than EBV infection
  - EBV-associated IM is most prevalent in 15-24 year olds in the United States
  - CMV-associated IM usually affects 20-30 year olds; age range is 18-66 years
- Age has significant impact on clinical expression
  - In young children, EBV is often asymptomatic or expressed as rashes, neutropenia, or pneumonia
  - Primary CMV in pregnant women may lead to congenital infection of neonate
Ethnicity
- EBV-associated IM is 30x more frequent in whites than blacks

Presentation

EBV and CMV are spread through intimate contact
- Often by asymptomatic shedders of virus to susceptible individuals
  - Spread through kissing, sharing of food, other intimate contact
- Transmitted by blood transfusions and open heart surgery
  - Risk increases with increased volume of blood transfused
  - CMV also transmitted with leukocyte transfusions
  - Risk reduced when blood is screened for antibodies or with use of leukocyte-filtered/-reduced products
Symptoms of IM
- EBV
  - Triad of sore throat, fever, lymphadenopathy
  - Symmetrical, slightly tender lymphadenopathy, especially posterior cervical region in adolescents
  - Hepatosplenomegaly, jaundice, rash
  - Malaise, headache, myalgias, chills, nausea
  - Studies suggest incubation period of 30-50 days
- CMV
  - Systemic symptoms (typhoidal)
  - Persistent fever may predominate (average duration ~ 19 days)
  - Pharyngitis and tonsillitis are rare
  - Often mild asymptomatic hepatitis
  - Lymphadenopathy or splenomegaly is uncommon but may occur
  - Interstitial pneumonia is a rare complication, especially in stem cell recipients

Laboratory Tests

CBC and peripheral blood smear
- Peripheral blood smear findings often precede heterophile antibody positivity in EBV infection
- Morphologic findings help in making diagnosis
  - Confirmation of EBV infection is required in heterophile negative cases
  - Diagnosis of CMV infection requires laboratory confirmation
Heterophile antibody (monospot) test
- Positive
  - Majority of EBV-associated IM
  - 90% of adolescents, 80% of children > 4 years of age
  - EBV-specific serology unnecessary to make diagnosis
  - Occasional patients with lymphoma or hepatitis are positive
- Negative
  - 50% of young children with symptomatic EBV infection
EBV-specific antibody test by indirect immunofluorescence
- Acute EBV infection
  - Elevated IgM antibody to anti-viral capsid antigens (VCAs) detected in 80% of children > 4 years
  - Anti-early antigens (anti-EAs)
  - Antibody to EBV nuclear antigen (EBNA) 3-4 weeks after onset
- EBV viral load
  - EBV DNA quantitated with real-time PCR
  - Not usually necessary for diagnosis of IM
  - Helpful for evaluation of other EBV-associated diseases
CMV testing
- CMV pp65 antigenemia assay
  - Detects CMV-infected leukocytes in blood
  - Results generally available within 24 hours
- Molecular tests for active infection
  - Quantitative PCR for viral load
  - Hybridization capture assay using RNA probes for CMV DNA
- Shell viral cultures using monoclonal probes to early antigens
Liver function tests
- Abnormal in almost all cases
- Maximum elevation in 2nd week of illness
Immunologic findings possible with EBV or CMV
- Cryoproteins or cold agglutinins
  - Slightly increased in 90-95% of patients with EBV infection
- Rheumatoid factor
- Antinuclear antibodies
- Anti-complement antibodies

Natural History

Most patients with IM recover without complications
- EBV IM spontaneously resolves in 2-3 weeks
Complications of EBV
- Autoimmune hemolytic anemia (< 3% of patients)
  - IgM-type cold agglutinin
  - Anti-i specificity in 20-70% of cases
- Splenic rupture
- Death
  - Rare; secondary to neurologic complications, splenic rupture, upper airway obstruction
CMV infection in immunocompetent individuals
- Infection is usually self-limiting with low mortality
CMV infection in immunosuppressed individuals
- Development of CMV pneumonia after transplantation or chemotherapy; may be life-threatening
Complications of secondary CMV infection
- Interstitial pneumonitis, hepatitis, Guillain-Barré syndrome, encephalitis, retinitis
- Gastrointestinal infections, pericarditis, myocarditis, myeloradiculopathy

MICROSCOPIC PATHOLOGY

EBV-Associated Peripheral Blood Findings

Mild to moderate leukocytosis (10-20 × 10⁹/L)
- Lymphocytosis ~ 1 week after initiation of symptoms
  - Peaks at 2-3 weeks
  - Persists up to 8 weeks
- Atypical lymphocytes with marked heterogeneity
  - Most common type is Downey type II cells
  - Next most common type is Downey type III cells
  - Frequently, cells intermediate between Downey type II and III cells are seen
  - Downey type I cells are most common in young children with EBV and other reactive causes
- Plasma cells are infrequent
- Mild thrombocytopenia (< 150 × 10⁹/L)
  - 1/3-1/2 of cases
- Autoimmune hemolytic anemia
  - Autoantibodies present (primarily anti-i)
  - Spherocytes and polychromasia
- Red blood cell clumping
  - Cold agglutinin
- Neutropenia is rare
  - Usually mild and self-limiting
    
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