Are You Confident of the Diagnosis?

What you should be alert for in the history

Sore throat, malaise and fatigue are the most common presenting symptoms. Rash, fever, and lymphadenopathy are common.

Characteristic findings on physical examination

Characteristic findings include pharyngitis with reddened/enlarged tonsils (exudative in >50% of cases). Tender lymphadenopathy is common (especially posterior cervical nodes). Fever (ranges from low-grade to high fevers) can be present. Periorbital/eyelid edema is is present in up to 50% of cases; palatal petechiae is present in up to 25%.

The incidence of rash ranges from 3%-9% and usually appears in the first few days of illness, lasting less than a week. It can take many forms inluding macular, papular, urticarial or morbilliform. More rarely, it can be petechial or vesicular. It usually occurs on the trunk and is less often seen on the palms. Erythema nodosum is rare. A classic extensive, morbilliform rash is seen in over 95% of patients with EBV infectious mononucleosis treated with amoxicillin/ampicillin (usually when mistaken for group A streptococcal pharyngitis). In this case, the rash may involve most of the body, inlcuding the palms and soles, and while this is not a true hypersensitivity reaction to penicillins, it is often misken as such (Figure 1). It generally lasts for a week or longer and desquamation may follow.

Continue Reading

Splenomegaly may be difficult to detect on examination (detected on physical exam in 15-65%), but is seen on ultrasound in the vast majority of cases. Hepatomegaly and/or jaundice may rarely occur and is more common in patients more than 40 years old. Occasionally, vaginal ulcers may be seen in females.

Figure 1.

A young female patient developed this macular papular rash with a few scattered petechiae after being treated with amoxicillin for a presumed strep throat infection. She was diagnosed with mononucleosis after the rash developed and further work up was performed.

Expected results of diagnostic studies

Common laboratory findings include:

Marked lymphocytosis (>50% leukocytosis) on blood smear with predominantly atypical lymphocytes. The presence of 10% atypical lymphocytes on peripheral-blood smear in a patient with suspected mononucleosis, has a sensitivity of 75% and specificity of 92% for the diagnosis. (Most laboratories will report the presence of atypcal lymphocytes when a peripheral blood smear is ordered.)

A rapid heterophile-antibody test (“monospot”) may be positive. Up to 25% are negative in 1 the first week of infection, but only 5-10% negative by the second week. Results are less likely to be positive in children under 12 years. Commercially available test kits are 70-92% sensitive and 96-100% specific. with clinical suspicion for infectious mononucleosis, a positive monospot has 85% sensitivity and 94% specificity for the diagnosis.

A definitive diagnosis can be made by testing serum antibodies against EBV viral capsid antigens (EBV VCA IgM/IgG), anti-EBV early antigen (EA IgG) and EBV nuclear antigen proteins (EBNA IgG). EBV VCA IgM is usually positive at time of presentation and disappears in 4-8 weeks after the infection onset.. EBNA IgG is usually not detectable until several weeks after illness onset. ALT/AST levels may be elevated, but hyperbilirubinemia is uncommon.

Diagnosis confirmation

The differential diagnosis for EBV infectious mononucleosis includes:

-Cytomegalovirus (CMV) causes a “heterophile antibody-negative” (monospot negative) infectious mononucleosis

-Herpes simplex virus (HSV) especially primary HSV infection, may cause gingivostomatitis and pharyngitis

-Coxsackievirus-A usually seen in young children (causes “hand-foot-mouth” disease and herpangina is classic)

-Human herpesvirus-6 (HHV-6)

-Primary/Acute HIV infection (human immunodeficiency virus) can present with pharyngitis, fever and hepatosplenomegaly. At this stage HIV ab testing will often be negative, but viral load will be very elevated and CD4 count will be low

-Group A Streptococcus pharyngitis (scarlatiniform rash without hepatosplenomegaly). Diagnosis made by pharyngeal swab culture

-Mycoplasma pneumoniae pharyngitis

-Diphtheria (caused by Corynebacterium diphtheriae, may see a classic gray “pseudomembrane” on the tonsils)

-Gonococcal pharyngitis (caused by Neisseria gonorroeae) is generally spread by oral to genital sexual contact and is rare in children, except in instances of sexual abuse

Many common repiratory viruses can cause pharyngitis (Rhinovirus, Coronavirus, Adenovirus, Influenza, Parainfluenza) In these cases, the pharyngitis is generally accompanied by “cold” and respiratory symptoms, including nasal congestion/rhinorrhea and cough, which would be absent in EBV “mono.”

Who is at Risk for Developing this Disease?

The majority of cases of infectious mononucleosis are due to primary infection with Epstein-Barr virus (EBV) Less commonly, infectious mononucleosis is attributed to cytomegolovirus (CMV) infection or other viruses. EBV occurs only in humans and results in lifelong (generally latent) infection

In developing countries and in lower socioeconomic groups in the developed world, primary EBV infection occurs in early childhood, generally manifesting as nonspecific illness. In developed countries, primary infection with EBV often leads to symptomatic mononucleosis in the second decade of life In the United States, the highest incidence is in 15- to 24-year olds

Primary EBV infection is rare in children under 1 year (likely due to passively transferred maternal antibodies). Epidemiologic surveys show that more than 95% of adults worldwide are infected with EBV.

What is the Cause of the Disease?

Heterophile-positive infectious mononucleosis is most commonly due to Epstein-Barr virus (EBV). EBV is a gammaherpesvirus.


Transmission of EBV is primarily through contact with infected saliva (hence the name “kissing disease”) and possibly by sexual transmission or blood transfusion. The iIncubation period is thought to be 30 to 50 days (from exposure to onset of symptoms). Infection likely begins in the epithelial cells of the oropharynx, thereby gaining access to lymphoid tissue of the pharynx, thereby infecting B lymphocytes. EBV infection persists in B lymphocytes with latently infected memory B lymphocytes serving as lifelong reservoirs of the virus. Intermittent, asymptomatic “shedding” of virus may be seen lifelong after initial infection.

Systemic Implications and Complications

Most patients recover without sequelae. The majority of clinical and laboratory signs of the disease resolve within 1 month. Lymphadenopathy and fatigue may persist longer. An ongoing fatigue syndrome (or “chronic fatigue syndrome”) has often been attributed to prior infectious mononucleosis, but this association is controversial and not well proven. Hematologic abnormalities may range from mild hemolytic anemia and thrombocytopenia to more severe conditions such as aplastic anemia, hemolytic-uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP).

Fulminant infection is uncommon, but can trigger hemophagocytic lymphohistiocytosis characterized by prolonged fever, lymphadenopathy, hepatosplenomegaly, rash, liver dysfunction and pancytopenia. .Neurologic complications are infrequent (<5%), but cases of Guillain-Barre syndrome, facial nerve palsy, peripheral neuritis, aseptic meningitis and transverse myelitis have been described after EBV infectious mononucleosis.

Although splenomegaly is common, splenic rupture is rare (0.5-1%) and may be life-threatening. Risk is greatly decreased by avoiding contact sports for at least 3 weeks after onset of symptoms. Upper airway obstruction due to lymphoid hyperplasia/mucosal edema is rare (<1%).

Treatment Options

There are no specific anti-EBV treatments for mononucleosis. Treatment options focus on supportive measures to alleviate symptoms

Optimal Therapeutic Approach for this Disease

Infectious mononucleosis is generally a self-limited disease and treatment consists of supportive care. Acetaminophen and non-steroidal anti-inflammatory agents (such as ibuprofen) may be used to manage fever and throat pain.

Acetaminophen dosing (Note: Use with caution in patients with preexisting liver disease)

Adults: 325-650mg po every 4-6 hrs OR 1gm po every 6-8 hrs as needed (not to exceed 4gm/24hr period

Children <12 yo: 10-15mg/kg/dose every 4-6hrs as needed (not to exceed 5 doses/24hr period)

Children >12 yo: refer to adult dosing

Ibuprofen dosing (Note: Use with caution in patients with aspirin sensitivity or renal disease, contraindicated in patients with history of GI bleeding or GI ulcers)

Adults: 200-600mg po every 6-8hrs as needed (Not to exceed 3.2gm/24hrs period)

Children <6 mos of age: not recommended

Children 6 mos-12yo: 5-10mg/kg/dose every 6-8hr as needed (not to exceed 40mg/kg/day)

Children >12 yo: refer to adult dosing.

Several small, double-blind, placebo-controlled trials and a recent Cochrane review have failed to show significant benefit from treatment with corticosteroids in infectious mononucleosis. Corticosteroids are reserved for cases of obstruction of the airway from tonsillar swelling, thrombotic throbocytopenia purpura (TTP), which may be rarely seen with mononucleosis, or for cases of hemophagocytic lymphohistiocytosis.

At present there are no recommended antiviral agents to treat infectious mononucleosis Randomized, controlled trials using acyclovir show transient reduction in viral shedding, but had no effect on the severity or duration of illness. A small (n=20) randomized study comparing valacyclovir with no treatment showed possible reduction in number and severity of symptoms, but further study is needed to confirm these findings. Attempts to develop an effective EBV vaccine have not yet been successful, but further trials are underway

Patient Management

Supportive care and patient education is the mainstay. Symptom management may be indicated. Adequate rest, fluid intake, and nutrition should be encouraged. Patients with mononucleosis should be advised to avoid physical exertion or participation in athletic activities (especially contact sports) for a minimum of 3-4 weeks, given the risk of splenic rupture (studies show risk drops dramatically 3 weeks after illness onset).

Special precautions (such as contact isolation) against transmission of EBV are not necessary. Although rest is encouraged, patients with mononucleosis may resume most normal activities (schoolwork) as soon as they feel able.

Unusual Clinical Scenarios to Consider in Patient Management

EBV is also associated with several other, less common, but distinct disorders including:

X-linked lymphoproliferative disease

Post-transplant lymphoproliferative disorder (PTLD), especially in liver and heart transplant recipients

Burkitt lymphoma

Nasopharyngeal carcinoma

Central nervous system (CNS) lymphoma

What is the Evidence?

Auwater, PG. “Infectious mononucleosis in middle age”. JAMA. vol. 281(5). 1999. pp. 454-59. (A grand rounds style presentation of a case of a more severe and prolonged case of infectious mononucleosis in a 42-year-old male, followed by a discussion of the condition, including diagnostic strategies, clinical features and suggestions for patient management. Highlights special considerations in making the diagnosis of primary EBV infection in middle-aged patients.)

Candy, B, Hotopf, M. “Steroids for symptom control in infectious mononucleosis”. Cochrane Database Syst Rev. vol. 3. 2006;July 19. pp. CD004402(The authors looked at seven randomized controlled trials (RCTs) comparing the effectiveness of corticosteroids when compared to placebo for symptom control in infectious mononucleosis and found insufficient evidence to recommend routine use of steroids for symptom control.)

Grotto, I, Mimouni, D, Huerta, M, Mimouni, M, Cohen, D, Robin, G. “Clinical and laboratory presentation of EBV positive infectious mononucleosis in young adults”. Epidemiol Infect. vol. 131. 2003. pp. 683-9. (A 4-year prospective study looking at the demographical, clinical and laboratory features of 330 young adult subjects with infectious mononucleosis due to EBV.)

Hurt, C, Tammaro, D. “Diagnostic evaluation of mononucleosis-like illnesses”. Am J Med.. vol. 120. 2007. pp. 911.e1-911. (Highlights the diagnostic challenges clinicians face when patients present with the “classic triad” of symptoms (fever, pharyngitis, and lymphadenopathy) of infectious mononucleosis. A systemic approach to the diagnosis of such illnesses is presented.

Johannsen, EC, Kaye, KM. “Epstein-Barr virus”. Mandell: Mandell, Douglas and Bennett’s principles and practice of infectious diseases. 2010. pp. 1993-5. (Textbook chapter on the virus and its clinical significance)

Luzuriaga, K, Sullivan, JL. “Infectious mononucleosis”. N Engl J Med. vol. 362. 2010. pp. 1993-2000. (A typical case of infectious mononucleosis is described, followed by a review of formal guidelines and discussions of clinical recommendations for care of patients.)

Macsween, KF, Higgins, CD, McAuley, KA, Williams, H, Harrison, N, Swerdlow, AJ. “Infectious mononucleosis in university students in the United Kingdom: Evaluation of the clinical features and consequences of the diseases”. Clin Infect Dis. vol. 50. 2010. pp. 699-706. (The authors followed college students diagnosed with infectious mononucleosis over a 2-year period while attending a university in the UK. The clinical features and consequences of the illness in this population were described.)