3.infectious Mononucleosis
3.infectious Mononucleosis
3.infectious Mononucleosis
(Kissing disease)
Summary
Infectious mononucleosis (IM), also called "mono" or the "kissing disease", is an acute condition caused
by the Epstein-Barr virus (EBV). The disease is highly contagious and spreads via bodily secretions,
especially saliva. Infection frequently goes unnoticed in children; mainly adolescents and young adults
exhibit symptoms. Symptomatic individuals typically first experience fever, malaise, and fatigue, which is
later accompanied by acute pharyngitis, tonsillitis, lymphadenopathy, and/or splenomegaly lasting up to
a month. IM is also sometimes associated with a measles-like exanthem, especially in individuals who
are falsely diagnosed with bacterial tonsillitis and given ampicillin or amoxicillin. To avoid misdiagnosis,
suspected cases are confirmed with a heterophile antibody test (monospot test), or in some cases,
positive serology. Patients exhibit lymphocytosis, often with atypical T lymphocytes on a peripheral
smear. IM is treated symptomatically, as it is usually self-limiting. Although complications are rare, IM is
associated with atraumatic splenic rupture due to splenomegaly and multiple malignancies (e.g.,
Hodgkin's lymphoma, Burkitt lymphoma).
Epidemiology
Etiology
Pathophysiology
EBV infects B lymphocytes in mucosal epithelium (e.g., oropharynx, cervix) via the CD21
receptor → infected B lymphocytes induce a humoral (B-cell) as well as a cellular (T-cell)
immune response → an increased concentration of atypical lymphocytes in the bloodstream,
which are CD8+ cytotoxic T cells that fight infected B lymphocytes
Clinical features
Incubation period: ∼ 6 weeks [5]
Clinical course
o Symptoms typically occur in adolescents and young adults and last for 2–4 weeks.
o Young children are often asymptomatic.
Signs and symptoms
o Splenomegaly, fever, fatigue, malaise
o Pharyngitis and/or tonsillitis (reddened, enlarged tonsils covered in pus), palatal
petechiae
o Bilateral cervical lymphadenopathy (especially posterior) that may become generalized
and can, in severe cases, lead to airway obstruction
o Abdominal pain
o Possibly hepatomegaly and jaundice
o Maculopapular rash (similar to measles): The rash is caused by the infection itself in
about 5% of cases but is most commonly associated with the administration of
aminopenicillin (e.g., ampicillin, amoxicillin)
In most cases, a maculopapular rash occurs due to empiric administration of aminopenicillins, and not
due to EBV infection.
Hepatosplenomegaly
Infectious mononucleosis
Membranous tonsillitis
Monospot test
o Detects heterophile antibodies produced in response to EBV infection using RBCs from sheep or
horses
o Patient's serum is mixed with a solution of sheep/horse RBC in vitro
Positive test: cross-reaction between heterophile antibodies and sheep/horse RBCs →
agglutination
Negative test
No heterophile antibodies present → no cross-reaction → no agglutination
In some cases, the test can show negative results if it is performed too soon (i.e. within the first
1–2 weeks after symptom onset) and antibodies have not developed yet.
o Specificity of ∼ 100%, sensitivity of 85%
Laboratory analysis: elevated LDH and liver transaminases
Peripheral smear: lymphocytosis with > 10% atypical lymphocytes (in some cases, up to 90%)
Serology: indicated if IM is suspected but monospot testing is negative
o Anti-viral capsid antigen antibodies (anti-VCA)
Anti-VCA IgM: appears early and vanishes ∼ 3 months after infection
Anti-VCA IgG: appears after 2–4 weeks and persists for life
o Anti-EBV nuclear antigen-antibody (anti-EBNA-1) IgG
A 22-year-old patient presents with lymphadenopathy and absolute lymphocytosis in the differential
blood count. The blood smear shows atypical lymphocytes (1). Atypical lymphocytes are activated T cells
with a polymorphic nucleus and abundant basophilic cytoplasm. An inactive lymphocyte (2) is
comparatively smaller with a spherical nucleus and a thin basophilic cytoplasmic layer. Despite being
activated T cells, atypical lymphocytes strongly resemble monocytes (3) in terms of their appearance,
hence the name infectious mononucleosis.
Pathology
Paracortical expansion through numerous, large immunoblasts (B cells and T cells), later expanding
throughout the entire node
Atypical Reed-Sternberg-like cells may be observed, which is why the disease is sometimes mistaken for
Hodgkin disease.
Differential diagnoses
Tonsillitis is an important differential diagnosis that is often treated with aminopenicillins (e.g.,
ampicillin). However, if given to a patient with IM, the patient often develops a macular erythematous
rash after 5–9 days.
Treatment
Nervous system
o Guillain-Barré syndrome
o Meningoencephalitis
o Cranial nerve disorders (esp. CN VII)
o Primary CNS lymphoma
o Multiple sclerosis
Hematological system
o Hemophagocytic lymphohistiocytosis (HLH): a life-threatening hematologic disorder involving
pancytopenia and severe inflammation due to increased activity of cytotoxic T cells and
macrophages [16]
Other secondary causes: malignancy (e.g., colon cancer) [17]
Clinical features: fever, hepatosplenomegaly, weight loss
Laboratory findings: pancytopenia, ↑ serum ferritin, cholestasis
Bone marrow biopsy: phagocytosis of hematopoietic cells
o Autoimmune hemolytic anemia, thrombocytopenia
o TTP, HUS
o DIC
Other organ systems
o Upper airway obstruction due to oropharyngeal inflammation and enlarged lymph nodes
o Splenic rupture
o Oral hairy leukoplakia (typically in HIV patients)
o Acute renal failure
o Pericarditis/myocarditis
o Pneumonia
o Otitis media
Associated malignancies
o Burkitt lymphoma (BL), a non-Hodgkin lymphoma
Associated with EBV infection (EBNA-1 antigen) [18]
Endemic BL
Occurs mainly in Africa
Typically affects the jaw and facial bones
Sporadic BL: manifests with abdominal masses or bone marrow involvement
Immunodeficiency-related BL: similar to sporadic BL (typically in HIV patients)
o Hodgkin lymphoma
o Nasopharyngeal carcinoma (common in Asian adult population)
o Post-transplant lymphoproliferative disorder: a group of aggressive and rapidly progressive
complications of solid organ transplantation and allogeneic hematopoietic stem cell
transplantation
Associated with EBV reactivation in patients with severe immunosuppression (e.g., post-
transplantation medications)
Clinical features: fever, weight loss, fatigue, lymphadenopathy, hepatosplenomegaly
Commonly progresses to B-cell lymphoma: poor prognosis
Treatment: reduce immunosuppressive therapy
HIV patient with oral hairy
leukoplakia
References
1.Houldcroft CJ, Kellam P. Host genetics of Epstein–Barr virus infection, latency and disease. Rev Med
Virol. 2014; 25(2): p.71-84. doi: 10.1002/rmv.1816.|
2.Jarrett RF. Risk factors for Hodgkin's lymphoma by EBV status and significance of detection of EBV
genomes in serum of patients with EBV-associated Hodgkin's lymphoma.. Leuk Lymphoma. 2003; 44
Suppl 3: p.S27-32. doi: 10.1080/10428190310001623801.|
3.González Saldaña N, Monroy Colín VA, Piña Ruiz G, Juárez Olguín H. Clinical and laboratory
characteristics of infectious mononucleosis by Epstein-Barr virus in Mexican children.. BMC research
notes. 2012; 5: p.361. doi: 10.1186/1756-0500-5-361.|
4.Luzuriaga K, Sullivan JL. Infectious mononucleosis. N Engl J Med. 2010; 362(21): p.1993-2000. doi:
10.1056/nejmcp1001116.|
5.Dunmire SK, Grimm JM, Schmeling DO, Balfour HH Jr, Hogquist KA. The Incubation Period of Primary
Epstein-Barr Virus Infection: Viral Dynamics and Immunologic Events.. PLoS Pathog. 2015; 11(12):
p.e1005286. doi: 10.1371/journal.ppat.1005286.|
7.Sangueza-Acosta M, Sandoval-Romero E. Epstein-Barr virus and skin.. An Bras Dermatol. 2018; 93(6):
p.786-799. doi: 10.1590/abd1806-4841.20187021.|
8.Rubin E, Reisner HM. Essentials of Rubin's Pathology. Lippincott Williams & Wilkins; 2009
10.Wright DH, Addis BJ, Leong ASY. Diagnostic Lymph Node Pathology. Hachette UK Company; 2011
13.Becker JA, Smith JA. Return to play after infectious mononucleosis.. Sports health. 2014; 6(3): p.232-
8. doi: 10.1177/1941738114521984.|
15.Bar-Or A, Pender MP, Khanna R, et al. Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging
Immunotherapies. Trends Mol Med. 2019; 26(3): p.296-310. doi: 10.1016/j.molmed.2019.11.003.|
16.Larroche C. Hemophagocytic lymphohistiocytosis in adults: diagnosis and treatment.. Joint bone
spine. 2012; 79(4): p.356-61. doi: 10.1016/j.jbspin.2011.10.015.|
17.Oliveira C, Chacim S, Ferreira I, Domingues N, Mariz JM. Secondary Hemophagocytic Syndrome: The
Importance of Clinical Suspicion. Case Reports in Hematology. 2014; 2014: p.1-5. doi:
10.1155/2014/958425.|
18.Pannone G, Zamparese R, Pace M, et al. The role of EBV in the pathogenesis of Burkitt’s Lymphoma:
an Italian hospital based survey. Infect Agent Cancer. 2014; 9(1): p.34. doi: 10.1186/1750-9378-9-34.|