Larry Waterbury
Infectious Mononucleosis
Infectious mononucleosis is one of several infections that are caused by herpes viruses. Others include cytomegalovirus (CMV) infections, herpes simplex infections (see Chapters 102 and 117), and varicella-zoster infections (see Chapter 117).
Epidemiology and Pathogenesis
Epstein-Barr virus (EBV) is the cause of infectious mononucleosis (1,2), an acute febrile illness that, in the United States, affects primarily teenagers and young adults (age group between 15 and 25 years). Infection with the virus is extremely common; for example, >50% of college students of both sexes have antibodies to the virus, and each year 12% of college students who do not have antibodies to EBV develop them (most of them during the course of clinical mononucleosis) (3). Because of the ubiquity of exposure early in life, infectious mononucleosis is rare in people older than 35 years; when it does occur, it may present atypically (see below). The virus seems to be spread by oral contact, first infecting B lymphocytes in the oral pharynx that subsequently generate a T-cell response that results in atypical lymphocytosis in the peripheral blood.
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TABLE 58.1 Signs and Symptoms of Infectious Mononucleosis |
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Signs and Symptoms
Clinical illness usually begins after a 1- to 2-month incubation period. Classically, patients have pharyngitis, lymphadenopathy, splenomegaly, and marked atypical lymphocytosis. Table 58.1 lists the relative frequency of the characteristic signs and symptoms associated with the illness. Pharyngitis occasionally is extremely severe and often is accompanied by an exudate, which may be foul smelling. Rarely, it is so severe that it leads to respiratory obstruction. Of the few patients who do not have pharyngitis (especially children), most simply have a nonspecific febrile illness associated with malaise. Other patients have mild jaundice and a syndrome that mimics infectious hepatitis. Posterior cervical adenopathy is characteristic of almost all patients, and generalized lymph node enlargement often is present as well. Approximately 60% have an enlarged spleen. Some patients experience a protracted course with nonspecific symptoms, slightly to moderately tender lymphadenopathy, and splenomegaly that persist for weeks. Most patients are significantly improved after 3 weeks.
Patients usually present to the practitioner at the end of the first week with a nonspecific illness characterized by malaise and perhaps by anorexia, mild headache, and fever (up to 104°F). Adenopathy, splenomegaly, and pharyngitis usually appear at about this time and slowly resolve over the following weeks. However, as noted below, the classic
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laboratory features of the disease may not be present until the second or third week of the clinical illness. Patients older than 40 years tend to have more prolonged fever and less adenopathy than do young adults (4,5).
Laboratory Features
The hematocrit value usually is normal, although occasionally mild hemolysis and rarely a severe autoimmune hemolytic anemia are seen. The peripheral white cell count usually is elevated, reaching its height during the second and third weeks of the clinical illness. Early in the course there may be severe absolute neutropenia, and occasionally the absolute neutrophil count is <500/µL. The differential count of the white cells is characterized by an absolute lymphocytosis with large numbers (>10% of the total white cell population) of atypical lymphocytes (large lobulated or indented nuclei and vacuolated or bluish cytoplasm). The platelet count is normal to slightly decreased in most patients; severe thrombocytopenia occurs rarely. Slight increases in the activity of hepatic enzymes are common but never reach the height seen in viral hepatitis. However, older patients tend to have more marked hepatic dysfunction, and jaundice is common in this group (4).
Serologic Features
Diagnosis is based on the presence of typical clinical features and characteristic serologic tests. A number of different EBV antibodies have been identified (6). They are summarized in Table 58.2. Immunoglobulin M antibody to viral capsid antigen (IgM anti-VCA) appears within 1 to 6 weeks after onset of infection and disappears within 3 to 6 months. A rising titer during the first few weeks of clinical illness is the most useful, and generally the most easily available serologic, evidence of recent primary infection. Antibodies to the early antigen complex of EBV of the diffuse (D) type (known as anti-D antibodies) also appear early in primary infection and disappear by 2 to 3 months, but anti-D antibody testing is much less available than IgM anti-VCA testing. Heterophil antibodies (nonspecific antibodies secondary to the immune response to EBV) are elevated in most patients, peaking in weeks 2 to 5 of clinical illness. They are present in low titer for up to 1 year.
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TABLE 58.2 Serologic Evidence of Epstein-Barr Virus Infection |
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Differential absorption studies are needed to identify the presence of those heterophil antibodies that are specific for infectious mononucleosis (antibodies are absorbed by bovine red cells but not by guinea pig kidney). A number of rapid diagnostic tests are commercially available. Some use horse red cells in a latex agglutination assay (“Monospot” test), and others use enzyme-linked immunosorbent assays. In general, the kits are quite sensitive and specific and are the tests of choice for diagnosis (7). Most patients do not require EBV antibody testing. In patients with classic symptoms of infectious mononucleosis, a positive rapid test is sufficient serologic confirmation for clinical diagnostic purposes. From 5% to 10% of patients with clinical infectious mononucleosis and serologic evidence of recent primary EBV infection are heterophil antibody negative (7). Another 5% to 10% of patients with clinical features of infectious mononucleosis, also heterophil negative, have another illness (e.g., CMV infection, toxoplasmosis, hepatitis B, or human herpes virus type 6) (8). Phenytoin, isoniazid, carbamazepine, and minocycline in rare cases produce a mononucleosis type illness.
Complications
Severe complications of infectious mononucleosis are rare but do occur. They include neurologic problems (encephalitis, meningitis, peripheral neuropathy, Guillain–Barré syndrome), bacterial superinfection, and splenic rupture (9). The latter has resulted in occasional deaths, especially because the diagnosis is easily missed. The diagnosis should be suspected if the patient has a recent history of sudden, brief, sharp, abdominal pain. Occasional deaths also have been seen with severe pharyngitis and airway obstruction. All of these complications are even more rare when the mononucleosis syndrome is caused by an infectious agent other than the EBV (see below). The pharyngitis in infectious mononucleosis may closely resemble that of exudative streptococcal pharyngitis, and all patients should have throat cultures to rule out bacterial infection.
Treatment
No specific treatment exists for infectious mononucleosis. All that usually is necessary is patient education and
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supportive care. There is no evidence that prolonged bed rest is helpful. It is reasonable for patients to avoid strenuous activities until they feel strong enough to participate. Contact sports should be avoided if the spleen is tender or significantly enlarged. Because splenomegaly may persist for months, however, it seems unreasonable to avoid such sports until the spleen is no longer palpable. Although contacts occasionally develop infectious mononucleosis, there is no evidence that the disease is highly infectious, and patients should not be rigidly restricted from interpersonal contacts (3). Patients continue to shed the virus for up to 18 months after onset of the illness (10), but close personal exposure during this period only occasionally results in transmission of the disease.
Surgery may be needed for splenic rupture, although some cases have been handled with only transfusion support (9). Corticosteroids usually are reserved for patients with severe pharyngitis or impending airway obstruction (11) and other rare life-threatening complications of the illness. Controlled studies have not proved the clinical usefulness of steroids or steroids plus acyclovir (12,13).
Other Causes of the Mononucleosis Syndrome
Cytomegalovirus Infection
Although CMV infections may cause devastating clinical illness in the newborn (in utero) and in the immunocompromised host, infection in the noncompromised adult causes a clinical syndrome essentially indistinguishable from infectious mononucleosis, except that exudative pharyngitis is unusual in CMV infection. Unlike exposure to EBV, which has occurred in most adults in the United States by age 25 years, primary CMV infections usually occur at an older age, making CMV mononucleosis the most common cause of the mononucleosis syndrome in patients older than 30 years. Up to 50% of people older than 40 years have antibodies to CMV, although most do not have a history of infection. Diagnosis can be made by finding an increased titer of serum IgM antibody to CMV.
Toxoplasmosis
Acute toxoplasmosis usually is asymptomatic in people with normal immune responses but may cause a syndrome that resembles infectious mononucleosis. However, pharyngitis does not occur, and splenomegaly and lymphadenopathy usually are not as prominent. In addition, patients usually do not develop hepatitis or the hematologic manifestations of EBV infections. Diagnosis usually depends on serologic findings indicative of recent primary infection (presence of anti-IgM antibodies by an indirect fluorescent antibody test or demonstration of rising titers of IgG antibodies by indirect fluorescent antibody).
Other Infections
Conditions other than EBV, CMV, and toxoplasmosis can cause the mononucleosis syndrome (8). Some of these conditions include viral hepatitis (see Chapter 47), acute human immunodeficiency virus infection (see Chapter 39), and human herpesvirus 6 infection. Sometimes an etiologic agent cannot be identified even after extensive serologic testing. Table 58.3 suggests a stepwise plan for the serologic evaluation of patients with the mononucleosis syndrome. Seronegative patients need further evaluation only if symptoms persist for more than 1 to 2 weeks, if symptoms intensify, or if worrisome adenopathy persists (see The Undiagnosed Patient with Lymphadenopathy).
Chronic Fatigue Syndrome
Since 1985, there has been an epidemic in the United States, predominantly in young women, of an illness characterized universally by debilitating and persistent fatigue and by a host of other symptoms (sore throat, tender lymph nodes, myalgia, joint pain, headaches, malaise, impaired memory or concentration), many of them suggestive of EBV infection. Initially, people who complained of these symptoms were thought to have chronic mononucleosis because of the demonstration of antibodies to EBV in their blood. It soon became evident, however, that antibody titers to a number of viruses (retroviruses, CMV, human herpesvirus 6, Coxsackie B virus, measles) were elevated in the blood of these patients, casting doubt on the role of EBV as an etiologic agent of the illness. Extensive seroepidemiologic study by the Centers for Disease Control and Prevention has revealed no consistent association with any infectious agent (14). Therefore, the illness was renamed the chronic fatigue syndrome, and criteria were formulated for its diagnosis (15). It has become obvious that the prevalence of psychiatric illness (e.g., depression, somatoform disorder, anxiety) is increased considerably in patients with the syndrome, so it is tempting to believe that all the symptoms reflect underlying psychopathology. Studies have failed to identify differences between control subjects and cases in a host of tests of immunologic function (16). In addition to infectious agents, psychiatric illness, and immunologic dysfunction, other potential causes of chronic fatigue syndrome that have been considered include allergies, disturbances of the hypothalamic–pituitary–adrenal axis, neurally mediated hypotension, and nutritional deficiency. Affected patients likely will remain symptomatic indefinitely; they need the understanding and support of their families and their caregiver and specific attention to psychiatric problems when symptoms are manifest (see Chapters 21, 22, and 24). The likelihood of patients returning to totally normal function is low (17). Poor prognostic features include older age, more chronic illness, presence of comorbid psychiatric disease, and a persistent belief by
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the patient that the illness has a physical cause (18). Psychiatric intervention, especially cognitive therapy, may be helpful (19,20).
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TABLE 58.3 Stepwise Serologic Testing in the Diagnosis of the Cause of Mononucleosis Syndrome |
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Chronic Lymphocytic Leukemia
Clinical Features
Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the United States. It is primarily a disease of older men (21). Two thirds of patients are 60 years or older, and two to three times as many men are afflicted as are women. A mild tendency for the disease to segregate in families suggests that genetic factors play a role in its acquisition (22).
Many patients are asymptomatic when diagnosed (see below), but complaints of malaise and increased fatigability are common. Ultimately, most patients develop generalized lymphadenopathy and splenomegaly.
A persistent absolute lymphocytosis (> 10,000/µL for ≥3 months) is the hallmark of the disease. Lymphocyte counts as high as 200,000 to 300,000/µL are seen occasionally. Other tests (bone marrow aspiration, lymph node biopsy) ordinarily are not necessary to establish the diagnosis.
As the disease progresses, hypogammaglobulinemia, anemia, granulocytopenia, and thrombocytopenia may develop. Autoimmune disorders (autoimmune hemolytic anemia, thrombocytopenia, pure red cell aplasia) develop in 10% to 15% of patients.
Treatment and Course
The survival of patients with CLL correlates best with the stage of their disease at diagnosis (23, 24, 25). For example, asymptomatic patients with only an absolute lymphocytosis (approximately 25% of the patients) have an essentially normal life expectancy. Patients with lymphadenopathy alone have a median survival of 6 to 8 years (approximately 50% of patients), and patients with significant anemia or thrombocytopenia (approximately 25% of patients) have a median survival of 2 to 3 years. A number of other features, such as age (older, better) and performance status, help predict prognosis. Bone marrow infiltration pattern is prognostically useful (nodular better than diffuse). An elevated β2-microglobulin level carries a worse prognosis. There are genetic markers, such as chromosome abnormalities and the mutation status of the variable segment of the immunoglobulin heavy chain (mutated better than not), and surrogate markers for these factors, such as ZAP-70 (26).
The evidence on whether or not treatment influences survival is controversial, but treatment can be helpful in decreasing the severity of signs and symptoms in the later stages of the disease. Thus, stable asymptomatic patients with or without lymphadenopathy or splenomegaly may not require treatment. On the other hand, patients with marked constitutional symptoms (weight loss, severe malaise) or with symptomatic anemia or thrombocytopenia should be treated. For years, standard treatment of CLL included alkylating agents (e.g., chlorambucil) and prednisone. Later studies suggest that treatment of CLL
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with the purine analogue fludarabine results in a higher rate of remission (especially of complete remission) and in more prolonged remissions than does treatment with alkylating agents (although whether or not survival is improved is controversial) (27). Rituximab, a monoclonal antibody against the CD20 lymphocyte antigen, is another drug that may be useful for treatment of CLL. Aggressive treatment (including bone marrow and stem cell transplant) of early-stage disease in younger patients with CLL is under active investigation. Patients with autoimmune hemolysis and thrombocytopenia require more aggressive treatment with corticosteroids, and splenectomy sometimes is necessary in severely anemic or thrombocytopenic patients who are unresponsive to corticosteroids. A hematologist or medical oncologist should be consulted at the time of diagnosis of CLL and should be involved in the care of patients who require treatment.
Differential Diagnosis
A number of neoplastic conditions other than CLL may be associated with a chronic lymphocytosis, such as macro globulinemia, B- and T-cell lymphomas, hairy cell leukemia, prolymphocytic leukemia, and adult T-cell leukemia. The morphology of the cells, evaluation of peripheral lymphocyte surface markers by flow cytometry, or other manifestations of the disease usually lead to the correct diagnosis. These conditions should be managed in close consultation with an oncologist.
A syndrome has been recognized, most often in older people, characterized by clonal proliferation of large granular T lymphocytes (up to 10,000/µL) and, usually, chronic neutropenia (28). Anemia (rarely, red cell aplasia) and thrombocytopenia are uncommon. Lymphocytic infiltration of the bone marrow and spleen (with splenomegaly) is characteristic; lymph node involvement is rare. Some patients have coexistent seropositive rheumatoid arthritis. Most patients, with or without arthritis, have serologic abnormalities (e.g., in addition to increased titers of rheumatoid factor, antinuclear antibodies, polyclonal hypergammaglobulinemia, and circulating immune complexes). The major morbidity from the disease is caused by recurrent bacterial infections; otherwise, most patients require no treatment, and their mortality rate is low.
The Undiagnosed Patient With Lymphadenopathy: When to Recommend Lymph Node Biopsy
Lymphadenopathy is a common physical finding that is associated with multiple disease processes (29). The decision about when to biopsy an enlarged lymph node is difficult (30). The problem arises most often in younger patients. Older patients with localized lymphadenopathy unexplained by infection or inflammation should be assumed to have cancer until proven otherwise; therefore, the biopsy decision in older patients usually is easy. However, lymphadenopathy in children and young adults usually is caused by inflammation, and biopsy usually is not diagnostic. In such circumstances, the clinician often is concerned about the possible harm from a delayed diagnosis of a malignancy (Hodgkin disease or non-Hodgkin lymphoma most commonly) or a granulomatous condition (e.g., tuberculosis, sarcoidosis) for which specific treatment is indicated. However, harm can result from unnecessary biopsy. The procedure is associated with both psychologic and physical discomfort to the patient, and, most importantly, interpretation of the biopsy of a reactive node can be uncertain. The histology of reactive nodes, especially those encountered in the mononucleosis syndrome, can be difficult to interpret. Reed–Sternberg cells (ordinarily pathognomonic of Hodgkin disease) can be seen in the nodes of patients with infectious mononucleosis, and reactive nodes sometimes look like and are interpreted as diagnostic of Hodgkin disease or of non-Hodgkin lymphoma. Because of these problems, biopsy of a lymph node should be avoided in a patient with the mononucleosis syndrome if possible.
If a specific diagnosis cannot be made based on the clinical features and serologic studies, few reliable criteria are available to assist with the decision as to whether a biopsy is indicated. However, one helpful retrospective study reported that in the age range from 9 to 25 years, three variables were important in determining whether a lymph node biopsy might be diagnostic of an illness requiring specific treatment (31): the size of the node to be tested by biopsy, the presence or absence of ear/nose/throat
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symptoms, and the presence or absence of an abnormality on chest radiograph. Nodes >2 cm in diameter were more likely to contain important histologic information than were smaller nodes. An abnormal chest radiograph (adenopathy, infiltrate) in a patient with peripheral adenopathy correlated with useful biopsy information. Patients with cervical lymphadenopathy but without any ear/nose/throat symptoms were more likely to have a diagnostic lymph node biopsy. Unfortunately, no validated method differentiates patients with adenopathy whose biopsy would lead to definitive diagnosis and treatment from those whose biopsies would not be clinically useful, and to date no specific clinical factors reliably help practitioners identify those patients with adenopathy who should undergo biopsy. Table 58.4 summarizes some of the features that can be used, especially in the young patient, to help determine the advisability and timing of a lymph node biopsy.
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TABLE 58.4 When to Recommend Lymph Node Biopsy in the Teenager and Young Adult |
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Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.