Infectious Mononucleosis and Mononucleosis-like Disorders

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[edit] Infectious Mononucleosis and Mononucleosis-like Disorders

Nelson M. Gantz

A 19-year-old man presenting with malaise, fever, sore throat, and cervical lymphadenopathy should suggest the diagnosis of acute infectious mononucleosis. Supporting this diagnosis is a white blood cell count showing a lymphocytosis with atypical lymphocytes and a positive monospot test, which measures the presence of heterophile antibodies. In addition to the positive monospot test, this patient will develop virus-specific antibodies to the Epstein-Barr virus (EBV). In most cases, the diagnosis of EBV infectious mononucleosis is not difficult. Problems occur for the physician when the clinical findings are not classic and the monospot test is negative. Several disorders can cause a monospot-negative, mononucleosis-like illness including cytomegalovirus (CMV), EBV, toxoplasmosis, group A β-hemolytic streptococci, and human immunodeficiency virus (HIV).

This chapter reviews the epidemiology, clinical manifestations, diagnosis, complications, clinical course, and management of acute EBV infectious mononucleosis. The disorders that clinically mimic infectious mononucleosis are also discussed.

EBV is one of nine herpesviruses. The other viruses in this group include herpes simplex virus-1, herpes simplex virus-2, varicella-zoster virus, CMV, human herpesvirus-6A, human herpesvirus-6B, human herpesvirus-7, and human herpesvirus-8. EBV is a DNA virus that infects B lymphocytes and nasopharyngeal epithelial cells. The virus does not produce cytopathic changes in the infected cells. In response to EBV infection, numerous antibodies are produced including heterophile antibodies and virus-specific EBV antibodies.

[edit] EPIDEMIOLOGY

Antibodies to EBV are found in persons all over the world, and their prevalence is highest in lower socioeconomic groups. For example, in China by age 5 years, about 95% of persons have EBV antibodies, whereas in the United States and Great Britain the seropositive rate for EBV antibodies is about 50% by that age. Acute infectious mononucleosis is diagnosed most frequently in adolescents in higher socioeconomic groups.^[1] The incidence of acute infectious mononucleosis is highest in persons 15 to 24 years of age. The symptoms of acute EBV infection depend on the age during which the infection is acquired. Those acquiring an acute EBV infection before age 15 years usually have an asymptomatic infection or a mild “flulike” illness. Persons acquiring EBV infection after age 15 years usually have the typical acute infectious mononucleosis illness with fever, pharyngitis, malaise, and cervical and axillary lymphadenopathy.

[edit] METHODS OF TRANSMISSION

Using special techniques, EBV can be demonstrated in the pharynx of patients with acute infectious mononucleosis for up to 18 months after recovery from an acute illness. The virus also can be identified in throat washings from patients with leukemia or lymphoma, as well as renal transplant recipients. The virus is not highly contagious, and most cases probably are acquired from asymptomatic shedders after close contact. Exchange of saliva with kissing may be responsible for viral transmission; the disease has been called the “kissing disease.” The paradox of a high seroprevalence rate and low degree of contagion results because infected persons shed the virus for prolonged periods after an acute illness. Documented cases of intrafamilial transmission are unusual as are clusters of acute infectious mononucleosis. In experimental studies, the usual incubation period is 35 to 50 days in the adult. No precautions are required once an index case is identified. Acute infectious mononucleosis also can spread by a blood transfusion and is a cause for the postpump perfusion syndrome; however, most cases of postpump perfusion syndrome are caused by CMV.

[edit] CLINICAL MANIFESTATIONS

Classic acute infectious mononucleosis is an illness characterized by fever, sore throat, malaise, and lymphadenopathy. The clue to the diagnosis is a young adult with a “toxic” appearance with a pharyngitis of more than 3 days' duration with posterior cervical lymphadenopathy. Pharyngeal exudates are often present (50%) and palatal petechiae may be seen. Other complaints include headache, anorexia, myalgias, chills, nausea, and abdominal discomfort. On physical examination, in addition to the lymphadenopathy, fever, pharyngitis, and splenomegaly occur in 50% of patients. Other findings include hepatomegaly, jaundice, periorbital edema, and a rash. The skin rash does not have a characteristic pattern and may be erythematous, maculopapular, or petechial. Interestingly, when a patient with acute infectious mononucleosis is given the antibiotic ampicillin, a nonallergic skin rash occurs in about 90% of patients. A skin rash also occurs in patients with CMV mononucleosis who have been given ampicillin, although less often than in patients with acute EBV infectious mononucleosis. However, this difference is not the way to establish the diagnosis of acute EBV mononucleosis. Table 31-1 lists the symptoms and signs of acute infectious mononucleosis. In addition to posterior cervical adenopathy, patients may have submandibular, anterior cervical, axillary, and inguinal lymphadenopathy. Splenomegaly is present in 50% of patients and is usually maximal in size during the second week of illness. Splenic rupture is a rare complication of infectious mononucleosis, and trauma such as contact sports should be avoided during the first few weeks after diagnosis.^[2][3][4]

Table 31-1 Clinical Features of Acute Infectious Mononucleosis

[edit] DIAGNOSIS

Laboratory features of acute infectious mononucleosis include the presence of more than 50% lymphocytes with at least 10% atypical lymphocytes. Other causes of atypical lymphocytes include CMV infections, toxoplasmosis, viral hepatitis, rubella, roseola, mumps, and drug reactions. The total white blood cell count is usually in the range of 10,000 to 20,000 cells/mm³. A characteristic laboratory abnormality is the presence of heterophile antibodies. The term heterophile antibody refers to an antibody that reacts with an antigen of another species. These antibodies in patients with acute infectious mononucleosis react with sheep or horse red blood cells, but not guinea pig kidney cells. In contrast, heterophile antibodies found in patients with serum sickness react with guinea pig kidney cells. The heterophile antibody is detected in 90% of patients with acute infectious mononucleosis, but may require 3 weeks to become positive.^[5]

Most laboratories use the monospot test to detect heterophile antibodies. The heterophile antibody is an immunoglobulin M (IgM) antibody and is not directed against the EBV. The heterophile antibody usually disappears in most patients by 3 months, but rarely may persist longer. Thus the presence of a positive monospot test indicates an acute infection. There is no need to follow or repeat the monospot test because the titer or duration of the heterophile antibody response does not correlate with the clinical course of the illness. Rarely, false-positive monospot tests occur in patients with varicella, influenza, or lymphoma. The most frequent cause of a false-positive monospot test is laboratory error.

Approximately 80% to 90% of patients with EBV mononucleosis have a positive monospot test by the third week of illness. In the other 10% to 20% of patients, the diagnosis can be established by obtaining EBV antibody titers. EBV antibodies are listed in Table 31-2. There is usually no need to follow EBV serology by repeating the test because most of the antibody levels persist for life. However, the appearance of antibody to Epstein-Barr nuclear antigen (EBNA) in a patient with a prior negative EBNA antibody test is suggestive of a recent infection.^[6][7] Other laboratory abnormalities include mild liver function test dysfunction, mild thrombocytopenia, positive cold agglutinins, and the presence of cryoglobulins.

Table 31-2 Antibodies to Epstein-Barr Virus

[edit] COMPLICATIONS

The majority of patients with an acute EBV infection recover spontaneously in 3 to 4 weeks. Rarely, complications occur (Box 31-1). Splenic rupture, especially during the second or third week, can be life-threatening. Thrombocytopenia is common but severe thrombocytopenia with an intracerebral bleed has been reported only rarely. Neurologic complications occur in less than 1% of patients but can dominate the clinical picture. At the time of presentation in patients with central nervous system (CNS) disease, the monospot test can be negative, and the numbers of atypical lymphocytes are low or absent. Rarely, neurologic complications, splenic rupture, or upper airway obstruction results in death.

[edit] MANAGEMENT

Treatment of acute infectious mononucleosis is mainly supportive. Contact sports should be avoided during the initial 3 weeks of the illness to avoid splenic rupture. Corticosteroids may be useful in patients with impending airway obstruction, severe thrombocytopenia, or hemolytic anemia. A 1-to 2-week course of corticosteroid therapy usually is administered. For normal hosts, acyclovir or other antiviral agents are not appropriate therapies for this disorder. In a placebo-controlled study in normal hosts,^[8] the combination of acyclovir and corticosteroid therapy decreased oral EBV shedding but did not affect the clinical symptoms such as duration of illness or sore throat. If a throat culture reveals group A β-hemolytic streptococci, however, then antibiotic therapy should be given.

[edit] DIFFERENTIAL DIAGNOSIS OF MONONUCLEOSIS-LIKE SYNDROMES

Heterophile-negative and EBV-negative infectious mononucleosis can be caused by several disorders. The various disorders are listed in Box 31-2.^[9][10]

[edit] Cytomegalovirus

In most studies, CMV is the most frequent cause of this syndrome. Patients with CMV are usually older (mean age 28 years) than those with EBV infectious mononucleosis (peak age 17 years). Fever tends to be more prolonged in patients with CMV mononucleosis compared with that seen in patients with EBV infectious mononucleosis. Pharyngitis and lymphadenopathy occur more often in patients with EBV infectious mononucleosis, and are noted in only 20% of patients with CMV infectious mononucleosis. A rash occurs in about one third of patients with CMV mononucleosis. Atypical lymphocytes also can be present. The diagnosis of acute CMV can be established by demonstrating CMV IgM antibodies. However, this test is associated with both false-positive and false-negative results. A diagnosis by serology also can be made by showing a fourfold rise in CMV IgG antibody titers.^[11] Other methods of diagnosis include detection of CMV antigens in the blood using a shell vial assay or using the polymerase chain reaction (PCR) to identify CMV DNA. Isolation of CMV from saliva or urine is not proof of acute infection, since prolonged viral secretion often occurs for months or years.

[edit] Hepatitis

The prodrome of acute viral hepatitis can mimic acute EBV infection, although pharyngitis and lymphadenopathy are absent. Fever, malaise, myalgias, arthralgias, and a rash may occur. Atypical lymphadenopathy may be present. The diagnosis is suggested by the marked elevation in liver function tests. Diagnosis is established by obtaining the serologic tests for the hepatitis viruses.

[edit] Human Immunodeficiency Virus

HIV can produce a self-limited infectious mononucleosis-like illness 2 to 4 weeks after the virus is acquired. The illness is characterized by fever, sore throat, headache, anorexia, malaise, arthralgias, myalgias, and weight loss. A diffuse erythematous rash may occur. Symmetric lymphadenopathy is common.^[12] Laboratory abnormalities most often include leukopenia, lymphopenia, and thrombocytopenia. Atypical lymphocytes also may occur. Detection of HIV antibody by enzyme-linked immunosorbent assay (ELISA) may be negative during the first few weeks of an acute primary infection. HIV seroconversion usually occurs 3 months after the virus is acquired. During the acute primary HIV infection, which mimics EBV infectious mononucleosis, a transient decline in the CD 4 cell count may occur. Determination of serum p24 HIV antigen levels or use of the PCR to detect HIV virus may be useful to establish the diagnosis of HIV disease. Otherwise, if there is a suspicion of HIV infection, the HIV antibody test should be repeated over time.^[13]

[edit] Trichinosis

Trichinosis is acquired by eating raw or poorly cooked meat containing the viable larvae of Trichinella spiralis. The protean manifestations of trichinosis—fever, myalgias, malaise, and rash—may mimic the symptoms of infectious mononucleosis. Pharyngitis and lymphadenopathy are absent. Clues that suggest the diagnosis of trichinosis include diarrhea, periorbital edema, subconjunctival hemorrhages, eosinophilia, and a low or normal erythrocyte sedimentation rate. The diagnosis can be established by demonstrating antibodies 3 weeks after the infection using the bentonite flocculation test. A muscle biopsy is usually unnecessary, but when obtained from a tender muscle reveals the characteristic worm (see Chapter 30 ).

[edit] Malaria

A history of travel should alert the physician to the possibility of malaria. Features that suggest acute infectious mononucleosis include fever, chills, fatigue, myalgias, and arthralgias. Pharyngitis and lymphadenopathy are absent (see Chapter 30 ).

[edit] Toxoplasmosis

Acute toxoplasmosis can mimic EBV or CMV infectious mononucleosis in the normal host. Toxoplasmosis, however, causes less than 1% of mononucleosis syndromes. Clinical features include fever, malaise, myalgias, and sore throat. Cervical lymphadenopathy is a prominent feature. Atypical lymphocytes may be present. The diagnosis of toxoplasmosis is made by demonstrating IgM antibody to Toxoplasma. Acute toxoplasmosis in the normal host is a self-limited illness, and specific acute toxoplasmosis therapy is not indicated.^[14]

[edit] Lymphogranuloma Venereum

Lymphogranuloma venereum (LGV) is caused by a type of Chlamydia trachomatis designated as types L1, L2, and L3. The initial stage is characterized by a small, asymptomatic ulcerative lesion. In the secondary stage, lymphadenopathy and prominent constitutional symptoms may mimic infectious mononucleosis. The constitutional symptoms include fever, chills, anorexia, myalgias, and arthralgias. Inguinal lymphadenopathy occurs, but enlarged cervical lymph nodes and pharyngitis are lacking. Diagnosis of LGV usually is established by demonstrating an antibody rise to one of the LGV-specific types (see Chapter 29 ).

[edit] Secondary Syphilis

Constitutional symptoms such as fever, malaise, anorexia, pharyngitis, arthralgias, and painless lymphadenopathy occur in patients with secondary syphilis. A macular, maculopapular, and/or pustular rash, especially involving the palms and soles, strongly suggests the diagnosis. A characteristic feature is enlargement of the epitrochlear lymph nodes. The serologic tests for syphilis (rapid plasma reagin, Venereal Disease Research Laboratory, and fluorescent treponemal antibody absorption) are always positive in patients with secondary syphilis and will establish the diagnosis (see Chapter 29 ).

[edit] Lyme Disease

Lyme disease caused by Borrelia burgdorferi may resemble infectious mononucleosis in the early stages. Early symptoms include malaise, fatigue, headache, fever, arthralgias, myalgias, and sore throat. These constitutional symptoms may occur before and persist after the characteristic rash of erythema chronicum migrans (ECM) disappears. Lymphadenopathy also occurs and is usually regional but may be generalized. The diagnosis of Lyme disease in the presence of the rash of ECM is not difficult. In the absence of the rash, the diagnosis is based on the epidemiologic findings and correlating the clinical features of the illness with the serologic results (see Chapter 141 ).

[edit] Cat-Scratch Disease

Cat-scratch disease can resemble acute infectious mononucleosis. The infection is caused by a fastidious gram-negative bacillus identified as Bartonella henselae. The disease is characterized by a primary lesion, a papule or pustule, which develops 3 to 10 days after a cat scratch. The hallmark of the illness is chronic regional lymphadenopathy, which develops about 2 weeks after the cat scratch. Constitutional symptoms that mimic infectious mononucleosis include fever, fatigue, sore throat, headache, and anorexia. The diagnosis is suggested by the history of localized lymphadenopathy in a patient with cat contact or a scratch. The organism can be identified on a lymph node biopsy. A serologic test also may be helpful in establishing the diagnosis.

[edit] Subacute Bacterial Endocarditis

The clinical features of subacute bacterial endocarditis (SBE) can mimic several disorders such as malignancy, cerebrovascular accident, rheumatic disease, and infectious mononucleosis. Patients with SBE can present with fever, fatigue, anorexia, myalgias, and arthralgias. Pharyngitis and lymphadenopathy are absent. The diagnosis of SBE is made by obtaining three sets of blood cultures.

[edit] Yersinia Enterocolitica

Yersinia is a gram-negative bacillus that usually causes diarrhea and abdominal pain. The organism also can cause acute pharyngitis with fever not associated with diarrhea. The diagnosis can be established by cultures.^[15]

[edit] Brucellosis

Acute brucellosis can mimic infectious mononucleosis. Symptoms include malaise, headache, anorexia, myalgias, arthralgias, and fever. Lymphadenopathy and splenomegaly may occur. Because patients with brucellosis present with nonspecific symptoms, a history of an epidemiologic exposure to animals or dairy products is key to suspect the diagnosis. Cases are diagnosed by serology or culture.

[edit] Tularemia

Tularemia is caused by Francisella tularensis, a small, gram-negative rod. Most infections are acquired from the bite of an infected animal such as a rabbit. The illness can mimic acute infectious mononucleosis, with patients having fever, chills, malaise, fatigue, and sore throat. On examination, pharyngitis and cervical lymphadenopathy may be present. Although the organism can be identified by culture, most infections are diagnosed serologically.

[edit] Leptospirosis

Leptospirosis is a zoonosis with clinical features that can mimic acute infectious mononucleosis. Fever, headache, and myalgias may occur. A rash, lymphadenopathy, and hepatosplenomegaly may be present. Pharyngitis is present in about 20% of patients. A history of exposure to animals such as rats or dogs is an important clue to the diagnosis (see Chapter 30 ). Most infections are diagnosed serologically.^[16]

[edit] Other Disorders

Several other disorders, including human herpesvirus-6 infection, salmonella bacteremia, miliary tuberculosis, systemic lupus erythematosus, juvenile rheumatoid arthritis, and lymphoma, may at times mimic acute infectious mononucleosis.^[17] Drugs such as procainamide, isoniazid, and phenytoin also can be associated with a mononucleosis-like illness.

[edit] Chronic Fatigue Syndrome

Chronic fatigue syndrome (CFS) is a disorder characterized by fatigue for at least 6 months and a complex or other symptoms. The illness is not new but has attracted increased attention and controversy since the late 1980s. The cause of the syndrome is unknown. In addition to the presence of chronic relapsing fatigue present for at least 6 months, clinical features include low-grade fever, chills, sore throat, lymphadenopathy, myalgias, arthralgias, headache, sleep disturbances, decreased ability to concentrate, and decreased memory (see Chapter 142 ).

[edit] REFERENCES