Epstein-Barr Virus (EBV) Infectious Mononucleosis (Mono) Clinical Presentation

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 4-6 weeks. 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. Fevers due to EBV infectious mononucleosis may reach 103-104°F but are usually less than 102°F.  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.

The only predisposing risk factor for Epstein-Barr virus (EBV) infectious mononucleosis is close contact with an individual infected with EBV. Epstein-Barr virus 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.

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.
• Splenic tenderness may be present in patients with splenomegaly. Splenomegaly is a late finding in EBV infectious mononucleosis. Generalized adenopathy with prominent splenomegaly should suggest EBV infectious mononucleosis. Splenic enlargement returns to normal or near normal usually within 3 weeks after the clinical presentation. 
• 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.
• 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.
• 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.
• 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. Palatal petechiae may also be a sign of agranulocytosis caused by aplastic anemia or a lymphoreticular malignancy involving the bone marrow (eg, acute leukemias or lymphomas).
• 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.
• 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.
• 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 drug-induced rash which is usually pruritic and is prolonged. 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. Rash has also been seen with azithromycin, levofloxacin, piperacillin-tazobactam, and cephalexin.
• Lymphadenopathy -  Any or all chains may be enlarged in individuals with EBV infectious mononucleosis. Lymphadenopathy is always bilateral and symmetrical in all patients, including those presenting with generalized adenopathy. Bilateral posterior cervical adenopathy is most highly suggestive of EBV infectious mononucleosis.
• In rare cases, EBV infectious mononucleosis results in various unusual clinical manifestations, including encephalitis, pancreatitis, acalculous cholecystitis, myocarditis, mesenteric adenitis, myositis, and glomerular nephritis.
• Central nervous system (CNS) findings associated with EBV mononucleosis are rare but usually occur later in the course of the illness. 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.
• 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.
  • Epstein-Barr virus infectious mononucleosis is characterized by early and transient bilateral upper-lid edema. This finding was first described by RJ 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 ^[13]  is usually present for only the first few days of illness.

Meningoencephalitis

Meningoencephalitis is a very rare manifestation of EBV infectious mononucleosis. Patients who have unusual neurologic manifestations (eg, scalp tenderness, optic neuritis) usually have other features of EBV infectious mononucleosis, which should suggest the cause of the patient's neurologic symptoms. Neurologic manifestations as the sole indication of EBV infectious mononucleosis are rare. The diagnosis of EBV infectious mononucleosis is a syndromic diagnosis, which is based on the association of fever, pharyngitis, and lymphadenopathy in conjunction with the characteristic hematologic abnormalities of EBV infectious mononucleosis. 

Malignancy

After resolution of the acute viral syndrome, EBV persists as memory T cells in the blood of all virus carriers where it exists as a latent, asymptomatic infection. ^[14]  Malignancy may occur in patients with latent EBV infections if EBV-induced B-lymphocyte proliferation becomes uncontrolled. ^[15]  Malignancies associated with EBV include nasopharyngeal carcinoma, gastric carcinoma, Hodgkin lymphoma, Burkitt lymphoma, and Leiomyomas and leiomyosarcomas in immunocompromised children - all major contributors to the disease burden of EBV. ^[16]

Selective immunodeficiency to EBV, which occurs in persons with X-linked lymphoproliferative syndrome, may result in severe, prolonged, or even fatal infectious mononucleosis.

Epstein-Barr virus infection is associated with certain malignancies that are described briefly as follows:

Burkitt's Lymphoma (BL)  is a highly aggressive B cell neoplasm characterized by the translocation and deregulation of the MYC gene on chromosome 8. Three distinct clinical forms of BL are recognized: endemic, sporadic, and immunodeficiency-associated forms. ^[17]  It is the most common childhood malignancy in equatorial Africa and Papua New Guinea and is characteristically localized to the jaw. The role of EBV infection in the development of BL is poorly understood. Epstein-Barr virus infection in BL displays a latent infection phenotype, characterized by the lack of expression of the EBV transforming proteins LMP-1 and EBNA-2. Chronic EBV infection appears to play a role in virtually all cases of endemic (African) BL ^[18]  and a minority of sporadic and immunodeficiency-associated BL. ^[19]  Antibodies to early antigen restricted (EA-R) are only occasionally detected in patients with infectious mononucleosis, but are often found at elevated titers in patients with African BL or chronic active EBV infection.

Hodgkin lymphoma (HL)  can be divided into classical HL (cHL) and nodular lymphocyte predominant HL. Though NLPHL is rarely EBV-positive, the link with EBV is fairly well established. The precise mechanisms by which EBV contributes to HL pathogenesis are uncertain, but EBV gene products may replace one of the genetic alterations that are required for the development of HL. ^[15]  Epstein-Barr virus-infected tumor cells express a subset of EBV genes, some of which are suspected as contributing to aberrant signaling, suppression of apoptosis, and immune evasion by Hodgkin/Reed-Sternberg (HRS) cells. ^[20]

Nasopharyngeal carcinoma  - is one of the most common cancers in southern China. Epstein-Barr virus (EBV) latency is universally associated with the undifferentiated subtype of nasopharyngeal carcinoma. ^[21]  Furthermore, the association of EBV with nasopharyngeal carcinoma is consistently seen in both low- and high-incidence areas. ^[22]  Levels of EA-D antibodies are elevated in patients with nasopharyngeal carcinoma. IgA antibodies to EBV antigens have proved useful for the identification of patients with nasopharyngeal carcinoma and of persons at high risk for the disease. EBV DNA detected in cell-free plasma in patients with NPC has been noted to be a prognostic marker of residual disease post-therapy and predictor of disease-free and overall survival. ^[21]

Diffuse Large B-cell lymphoma  - Epstein-Barr virus–positive diffuse large B-cell lymphoma (EBV-positive DLBCL) was entered as a provisional entry in WHO classification system in 2008, ^[23]   which was later revised to include “not otherwise specified” (NOS). This is a subtype of B cell lymphoma demonstrating numerous large EBV+ B cells and that often involves extranodal sites in apparent immunocompetent patients. Epstein-Barr virus-positive DLBCL accounts for 8% to 15% of DLBCL in the Asian population and approximately < 5% in the western population. ^[23]  The prognosis of EBV+ DLBCL is poor, with a median survival of 2 years. 

Leiomyosarcoma  – Epstein-Barr virus-associated smooth muscle tumors are rare with a high incidence in immunocompromised patients such as HIV. ^[24]   There may be multiple smooth muscle tumors, often found in uncommon locations such as the central nervous system (CNS), lung, pericardium, pleura, spleen, adrenal gland, lymph node, and orbit. High levels of EBV genomes have been found in tumor tissue. ^[25]  AIDS-associated leiomyosarcomas behave in an aggressive fashion and frequently recur despite therapy, resulting in poor survival. ^[26]

Non-Hodgkin’s lymphoma (NHL) - Individuals infected with HIV and EBV also tend to have higher incidence of NHL. The significant immune system defects in HIV, especially cytotoxic lymphocytes controlling EBV induced proliferation, appear to play a role.

Chronic Active EBV (CAEBV)

Another contributor to EBV-related morbidity is Chronic Active Epstein-Barr virus (CAEBV). The revised World Health Organization (WHO) classification defined CAEBV as a chronic, active EBV infection of T- and NK-cell types. ^[27]   This is a disease of exclusion. Chronic Active Epstein-Barr virus is characterized by persistent inflammatory symptoms such as fever, lymphadenopathy, liver dysfunction, mononucleosis-like symptoms for more than 3 months, elevated EBV DNA PCR in peripheral blood, infiltration of tissues by EBV positive lymphocytes, and skin lesions hydroa vacciniforme. ^[12]

Posttransplantation lymphoproliferative disorders:

Posttransplantation lymphoproliferative disorders encompass a wide spectrum of disease, and most frequently present as diffuse large B-cell lymphoma, Burkitt lymphoma, and plasmablastic lymphoma. ^[27]  Epstein-Barr virus is the most common cause, and the condition is seen in EBV-negative recipients who develop primary EBV infection, usually from a graft from an EBV-positive donor. More than 90% of PTLD cases are associated with re-activation of latent EBV in the setting of post-transplant pharmacologic immunosuppression; despite advances, prognosis for affected patients remains poor. ^[28]