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

 General: Approx. 90–95% of adults are EBV-seropositive worldwide. [1]

 Peak incidence (of symptomatic disease): 15–24 years of age [2]
 Incidence: 5/1000 per year [3]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

 Pathogen: Epstein-Barr virus (EBV), also called human herpesvirus 4 (HHV-4)

  Transmission: Infectious mononucleosis spreads via bodily secretions, especially saliva.
Therefore, it is also called kissing disease.

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

“You must Be (B lymphocytes) 21 (CD21) to drink in a BAR (Epstein-BARr virus).”

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)

Splenomegaly can lead to a potentially life-threatening splenic rupture!

In most cases, a maculopapular rash occurs due to empiric administration of aminopenicillins, and not
due to EBV infection.

Hepatosplenomegaly

CT abdomen (coronal section) of a patient with HIV-associated visceral leishmaniasis

The liver and the spleen are enlarged. Multiple, nodular hypodense lesions are visible throughout the
spleen.

Infectious mononucleosis

The tonsils are significantly

enlarged. A thick, yellow-white
membrane is visible over the
tonsils and uvula. The palatal
mucosa appears inflamed,
especially in the midline.

This is the typical appearance of

tonsillitis in infectious
mononucleosis, which is caused by
the Epstein-Barr virus.

Membranous tonsillitis

Enlarged, inflamed tonsil (green

overlay) with gray-white
deposits (white outline) in a
patient with infectious
mononucleosis.

Exudative tonsillopharyngitis in infectious

mononucleosis

Tonsillopharyngitis caused by Epstein-Barr virus. Both

tonsils are so massively enlarged that they touch, which
is called kissing tonsils. They are covered with the
characteristic white-grayish deposits (pus).
Diagnostics

Clinical suspicion of IM is confirmed via antibody testing.

 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

Serology Past infection Primary infection

anti-VCA IgM negative positive

anti-VCA IgG positive positive

Anti-EBNA-1 IgG positive negative

Atypical lymphocytosis in infectious mononucleosis

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

 Lymph nodes show:

Reactive follicular hyperplasia due to increased activation of B lymphocytes

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

 Mononucleosis-like syndromes [12]

o Streptococcal pharyngitis, tonsillitis
o Acute HIV infection
o CMV infection (CMV mononucleosis)
o Viral hepatitis
o Toxoplasmosis
 Diphtheria
 Acute leukemia

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

Therapy of IM is mainly symptomatic.

 Avoid physical activity because of the risk of splenic rupture.

o Patients should avoid strenuous physical activities for at least 21 days after initial
symptoms develop.
o Patients should avoid high-contact sports (e.g., football, wrestling) for at least 4 weeks
 Fluids (IV administration if necessary)
 Analgesics/antipyretics (e.g., acetaminophen), viscous lidocaine for throat pain
 Steroids are not recommended for routine use but may be considered in complicated cases.
 Contact persons should avoid direct contact to the patient's bodily fluids (e.g., no sharing of
food, drinks, personal items, no kissing)
Complications

Immunocompromised patients have a higher risk of developing complications. [14]

 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

A 3–5 cm confluent, white

plaque with a hairy appearance
is seen across the left lateral
side of the tongue that, in this
case, could not be scraped off
using a spatula.

This clinical finding is

characteristic of oral hairy
leukoplakia.

Anterior mediastinal mass in Hodgkin

lymphoma

X-ray chest (a: PA view; b: left lateral

view) and CT chest (c. with contrast;
coronal plane) of a patient with
nodular sclerosing Hodgkin lymphoma

The PA radiograph shows an abnormal

superior mediastinum that is dense,
markedly widened, and lobulated
(green overlay). On the lateral
radiograph, there is opacification of
the retrosternal space, which should
normally be a clear area. CT confirms
the presence of a large anterior locally
invasive mediastinal soft tissue mass
(arrows).
Li: liver; LV: left ventricle

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.|

6.Incidence of rash after amoxicillin treatment in children with infectious mononucleosis.

https://www.ncbi.nlm.nih.gov/pubmed/23589810. Updated: May 1, 2013. Accessed: March 17, 2017.

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

9.Infectious mononucleosis: histopathologic aspects. https://www.ncbi.nlm.nih.gov/pubmed/170576.

Updated: January 1, 1975. Accessed: March 17, 2017.

10.Wright DH, Addis BJ, Leong ASY. Diagnostic Lymph Node Pathology. Hachette UK Company; 2011

11.Infectious mononucleosis. The spectrum of morphologic changes simulating lymphoma in lymph

nodes and tonsils.. https://www.ncbi.nlm.nih.gov/pubmed/3812872. Updated: February 1, 1987.
Accessed: March 17, 2017.

12.Mononucleosis-Like Syndrome. http://www.fpnotebook.com/id/virus/MnclsLkSyndrm.htm. Updated:

March 3, 2017. Accessed: March 17, 2017.

13.Becker JA, Smith JA. Return to play after infectious mononucleosis.. Sports health. 2014; 6(3): p.232-
8. doi: 10.1177/1941738114521984.|

14.Epstein-Barr Virus and Infectious Mononucleoisis. https://www.cdc.gov/epstein-barr/hcp.html.

Updated: September 14, 2016. Accessed: March 28, 2017.

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.|