Infectious Mononucleosis

Introduction

Background

Infectious mononucleosis was first described by Sprunt and Evans in the Bulletin of the Johns Hopkins Hospital in 1920.¹ They described the clinical characteristics of Epstein-Barr virus (EBV) infectious mononucleosis. At the time, their article was entitled "Mononuclear leukocytosis in reaction to acute infection (infectious mononucleosis)," because the causative organism, EBV, had yet to be described.

Since the 1800s, infectious mononucleosis has been recognized as a clinical syndrome consisting of fever, pharyngitis, and adenopathy. The term glandular fever was first used in 1889 by German physicians and was termed Drüsenfieber. The association between infectious mononucleosis and EBV was described in the late 1960s.

Pathophysiology

EBV is transmitted via intimate contact with body secretions, primarily oropharyngeal secretions. EBV infects the B cells in the oropharyngeal epithelium. The organism may also be shed from the uterine cervix, implicating the role of genital transmission in some cases. On rare occasion, EBV is spread via blood transfusion.

Circulating B cells spread the infection throughout the entire reticular endothelial system (RES), ie, liver, spleen, and peripheral lymph nodes. EBV infection of B lymphocytes results in a humoral and cellular response to the virus. The humoral immune response directed against EBV structural proteins is the basis for the test used to diagnose EBV infectious mononucleosis. However, the T-lymphocyte response is essential in the control of EBV infection; natural killer (NK) cells and predominantly CD8⁺ cytotoxic T cells control proliferating B lymphocytes infected with EBV.

The T-lymphocyte cellular response is critical in determining the clinical expression of EBV viral infection. A rapid and efficient T-cell response results in control of the primary EBV infection and lifelong suppression of EBV.

Ineffective T-cell response may result in excessive and uncontrolled B-cell proliferation, resulting in B-lymphocyte malignancies (eg, B-cell lymphomas).

The immune response to EBV infection is fever, which occurs because of cytokine release consequent to B-lymphocyte invasion by EBV. Lymphocytosis observed in the RES is caused by a proliferation of EBV-infected B lymphocytes. Pharyngitis observed in EBV infectious mononucleosis is caused by the proliferation of EBV-infected B lymphocytes in the lymphatic tissue of the oropharynx.

Frequency

United States

EBV infectious mononucleosis is a common cause of viral pharyngitis in patients of all ages, but it is particularly frequent in young adults. In the United States, approximately 50% of the population seroconverts before age 5 years, with much of the rest seroconverting in adolescence or young adulthood. Approximately 12% of susceptible college-aged young adults convert each year, half of whom develop acute infectious mononucleosis.

International

See United States.

Mortality/Morbidity

• Patients with EBV infection who present clinically with infectious mononucleosis invariably experience accompanying fatigue. Fatigue may be profound initially but usually resolves gradually in 3 months. Some patients experience prolonged fatigue and, after initial recovery, enter a state of prolonged fatigue without the features of infectious mononucleosis.
• Mortality and morbidity rates due to uncomplicated primary EBV infectious mononucleosis are low. The rare cases of attributed mortality are usually related to spontaneous splenic rupture. Splenic rupture may be the initial presentation of EBV mononucleosis.
• Most cases of EBV infectious mononucleosis are subclinical, and the only manifestation of EBV infection is a serological response to EBV surface proteins discovered with EBV serological tests. Airway obstruction and central nervous system (CNS) mononucleosis are also responsible for increased morbidity in infectious mononucleosis. Selective immunodeficiency to EBV, which occurs in persons with X-linked lymphoproliferative syndrome, may result in severe, prolonged, or even fatal infectious mononucleosis.
• Hepatic necrosis caused by extensive EBV proliferation in the RES of the liver is the usual cause of death in affected males. EBV is the main cause of malignant B-cell lymphomas in patients receiving organ transplants.
• Most instances of posttransplant lymphoproliferative disorder (PTLD) are associated with EBV. EBV in PTLD is acquired from an EBV-positive donor organ. The likelihood of PTLD is directly proportional to the degree of immunosuppressive drugs administered to the transplant patient.
• Depending on the intensity, rapidity, and completeness of the T-lymphocyte response, malignancy may result if EBV-induced B-lymphocyte proliferation is uncontrolled. Hodgkin disease and non-Hodgkin lymphoma (NHL) may result. Other EBV-related malignancies include oral hairy leukoplakia in patients with HIV infection.
• Leiomyomas and leiomyosarcomas in immunocompromised children, nasopharyngeal carcinoma, and Burkitt lymphoma are among other neoplasms caused by EBV.

Age

Although primarily a disease of young adults, EBV infectious mononucleosis may occur from childhood to old age.

Clinical

History

• Most patients with Epstein-Barr virus (EBV) infectious mononucleosis are asymptomatic and, therefore, have few if any symptoms. Most adults (approximately 90%) show serological evidence of previous EBV infection.
• The incubation period of EBV infectious mononucleosis is 1-2 months. Many patients cannot recall close contact with individuals with pharyngitis. Virtually all patients with EBV infectious mononucleosis report fatigue and prolonged malaise. A sore throat is second only to fatigue and malaise as a presenting symptom.
• Fever is usually present and is low grade, but chills are relatively uncommon. Arthralgias and myalgias occur but are less common than in other viral infectious diseases.
• Nausea and anorexia, without vomiting, are common symptoms.
• Various other symptoms have been described in patients with EBV infectious mononucleosis, including cough, ocular muscle pain, chest pain, and photophobia.
• Importantly, patients without CNS involvement experience no cognitive difficulties. CMV infectious mononucleosis rarely involves the CNS.
• Myalgias, which are uncommon, are rarely (if ever) severe.

Physical

• Physical findings in infectious mononucleosis should be viewed in terms of frequency distribution and time course after clinical presentation.
• Early signs include fever, lymphadenopathy, pharyngitis, rash, and/or periorbital edema. Relative bradycardia has been described in some patients with EBV mononucleosis, but it is not a constant finding.
• Later physical findings include hepatomegaly, palatal petechiae, jaundice, uvular edema, splenomegaly, and, rarely (1-2%), findings associated with splenic rupture.
• CNS findings associated with EBV mononucleosis are rare but usually occur later in the course of the illness.
• Splenic tenderness may be present in patients with splenomegaly.
• Pulmonary involvement is not a feature of EBV infectious mononucleosis.
• The classic presentation of EBV infectious mononucleosis in children and young adults consists of the triad of fever, pharyngitis, and lymphadenopathy.
• Older adults and elderly patients with EBV infectious mononucleosis often have few signs and symptoms referable to the oropharynx and have little or no adenopathy. Elderly patients with EBV mononucleosis present clinically as having anicteric viral hepatitis.
• Predictably, jaundice develops in less than 10% of young adults with EBV infectious mononucleosis, but jaundice may occur in as many as 30% of affected elderly individuals.
• The pharyngitis due to EBV infectious mononucleosis may be exudative or nonexudative.
  • Exudative pharyngitis is commonly confused with group A streptococcal pharyngitis, which is complicated further by the fact that approximately 30% of patients with EBV infectious mononucleosis have group A streptococcal carriage of the oropharynx. The unwary physician may incorrectly conclude that a throat culture or rapid test positive for group A streptococci in a patient with infectious mononucleosis represents streptococcal pharyngitis.
  • Nonexudative pharyngitis with or without tonsillar enlargement is common in patients with EBV infectious mononucleosis and resembles viral pharyngitis.
  • Patients with either exudative or nonexudative EBV infectious mononucleosis are commonly colonized by group A streptococci.
• Tonsillar enlargement is common, and massive tonsillar enlargement may be observed. The term kissing tonsils is used to describe extreme enlargement of both tonsils in patients with EBV infectious mononucleosis. Extreme tonsillar enlargement may result in airway obstruction.
• Palatal petechiae of the posterior oropharynx distinguish infectious mononucleosis from other causes of viral pharyngitis but do not distinguish it from group A streptococcal pharyngitis, in which palatal petechiae may occur.
• Uvular edema is an uncommon finding in infectious mononucleosis, but, if present, it is a helpful sign in distinguishing EBV infectious mononucleosis from other causes of viral pharyngitis or from group A streptococcal pharyngitis.
• Early in the course of EBV infectious mononucleosis, patients may present with a maculopapular generalized rash. The rash is faint and evanescent and rapidly disappears. It is nonpruritic. This is a marked contrast to patients mistakenly diagnosed with streptococcal pharyngitis who have been administered ampicillin or amoxicillin and then develop a maculopapular rash as a drug reaction. Drug-induced rash is usually pruritic and is prolonged, in contrast to the viral rash of EBV infectious mononucleosis. Patients with EBV infectious mononucleosis who experience drug reactions to beta-lactams are not allergic to these medications. Administration of beta-lactams after resolution of the infection does not result in drug fevers or rashes.
• Splenomegaly is a late finding in EBV infectious mononucleosis. Splenic enlargement returns to normal or near normal usually within 3 weeks after the clinical presentation.
• In rare cases, EBV infectious mononucleosis results in various unusual clinical manifestations, including encephalitis, pancreatitis, acalculous cholecystitis, myocarditis, mesenteric adenitis, myositis, and glomerular nephritis.
• Neurologic syndromes due to EBV infectious mononucleosis include optic neuritis, transverse myelitis, aseptic meningitis, encephalitis, meningoencephalitis, cranial nerve (CN) palsies (particularly CN VII), and Guillain-Barré syndrome.
• Although EBV-induced antibodies to RBC membranes may occur, clinical anemia is uncommon with EBV infectious mononucleosis.
• Leukocytosis, rather than leukopenia, is the rule in infectious mononucleosis.
• Periorbital edema is an uncommon, and therefore fairly specific, physical finding in infectious diseases.
  • Bilateral periorbital edema not associated with generalized edema (eg, nephrotic syndrome) suggests trichinosis, Kawasaki disease, allergic reactions, or bilateral periorbital cellulitis.
  • Unilateral periorbital edema suggests conditions such as thyrotoxicosis, retro-orbital eye tumor, Chagas disease, insect sting, or unilateral conjunctivitis.
  • EBV infectious mononucleosis is characterized by early and transient bilateral upper-lid edema. In contrast to the disorders mentioned above, which are either unilateral or bilateral and involve the periorbital area, with or without the eyelids, the external eye involvement of EBV infectious mononucleosis is characterized by bilateral upper-lid edema. This finding was first described by Hoagland and is referred to as Hoagland sign. Hoagland noted the association of EBV infectious mononucleosis in young military recruits with EBV infectious mononucleosis. Hoagland sign may be detected when patients look in the mirror early in the course of their illness or when the astute physician notices this early in the clinical presentation. Hoagland sign is present for only the first few days of illness and should not be sought later in the course of the infectious process.

Table 1. Differential Diagnoses of Infectious Mononucleosis

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Table

Clinical Parameters		Epstein-Barr Virus	Cytomegalovirus	Toxoplasmosis	Viral Hepatitis
Symptoms	Fatigue	+++	+	+/-	+
	Malaise	++	+	-	+
	Mild sore throat	+	+	+/-	+/-
	Early maculopapular rash	±	-	-	+/-
Signs	Early bilateral upper eyelid edema	±	-	-	-
	Unilateral localized adenopathy	-	-	+	-
	Bilateral posterior cervical adenopathy	+	+	-	+/-
	Tender hepatomegaly	+/-	+/-	-	+
	Splenomegaly	+	+/-	+/-	-
Laboratory abnormalities	WBC count	N*/-	N/-	N	¯
	Elevated SGOT†/SGPT‡	++	+	+/-	+++
	Atypical lymphocytes (>10%)	+	+	-	-
	Thrombocytopenia	+/-	+/-	-	+/-
	Elevated IgM§ CMV titer	-	+	-	-
	Elevated IgM EBV VCAII titer	+	-	-	-
	Elevated IgM toxoplasmosis titer	-	-	+	-
	Elevated hepatitis (eg, A, B, D) IgM titer	-	-	-	+

Clinical Parameters		Epstein-Barr Virus	Cytomegalovirus	Toxoplasmosis	Viral Hepatitis
Symptoms	Fatigue	+++	+	+/-	+
	Malaise	++	+	-	+
	Mild sore throat	+	+	+/-	+/-
	Early maculopapular rash	±	-	-	+/-
Signs	Early bilateral upper eyelid edema	±	-	-	-
	Unilateral localized adenopathy	-	-	+	-
	Bilateral posterior cervical adenopathy	+	+	-	+/-
	Tender hepatomegaly	+/-	+/-	-	+
	Splenomegaly	+	+/-	+/-	-
Laboratory abnormalities	WBC count	N*/-	N/-	N	¯
	Elevated SGOT†/SGPT‡	++	+	+/-	+++
	Atypical lymphocytes (>10%)	+	+	-	-
	Thrombocytopenia	+/-	+/-	-	+/-
	Elevated IgM§ CMV titer	-	+	-	-
	Elevated IgM EBV VCAII titer	+	-	-	-
	Elevated IgM toxoplasmosis titer	-	-	+	-
	Elevated hepatitis (eg, A, B, D) IgM titer	-	-	-	+

*Normal
^† Serum glutamic-oxaloacetic transaminase
^‡ Serum glutamic-pyruvic transaminase
^§ Immunoglobulin M
^II Viral capsid antigen

Causes

• The only predisposing risk factor for EBV infectious mononucleosis is close contact with an individual infected with EBV.
• EBV commonly persists in oropharyngeal secretions for months after clinical resolution of EBV infectious mononucleosis.
• Patients with congenital immunodeficiencies are predisposed to EBV-induced lymphoproliferative disorders and malignancies.
• Acquired immunodeficiencies due to the effects of immunosuppression (eg, PLDT) or infectious disease-induced immunosuppression (ie, HIV) may predispose to oral hairy leukoplakia or non-Hodgkin lymphoma.
• Burkitt lymphoma has a distribution (ie, in Africa) that is the same as the distribution of malaria. The geographic location predisposes to Burkitt lymphoma in children.