Infectious mononucleosis (IM) is a familiar disorder to physicians who treat adolescents. It is usually an acute, se If- li m i ted, benign lymphoproliferative disease, easily recognized by its classic presentation, and represents primary Epstein-Barr virus (EBV) infection. This article reviews the etiology, epidemiology, and characteristic triad of clinical, laboratory, and serologie features of IM1 and then focuses on management. Specific issues considered include how to proceed if the heterophile antibody test is negative, how to predict the duration of illness in individual patients and counsel their return to school and activities, and when, if ever, to administer steroids.
ETIOLOGY AND EPIDEMIOLOGY
The causative agent of IM is EBV, but the term infectious mononucleosis is not synonymous with EBV infection, since EBV is capable of producing clinical disorders other than IM. The clinical manifestations of primary EBV infection tend to be agerelated; asymptomatic or mild illness in young children and the acute syndrome of IM in adolescents and young adults. Infectious mononucleosis is traditionally defined as the triad of:
* clinical features including fever, malaise, lymph node enlargement, and tonsillopharyngitis,
* laboratory features including a lymphocytosis with atypical lymphocytes, and
* serologie features, such as the presence of heterophile antibodies.
Although EBV is a ubiquitous vims found throughout the world, IM is seen primarily in developed countries. This is a reflection of the age at which primary EBV infection occurs: children in developing countries acquire their primary EBV infection at an early age - 90% se roc on verting in the first 6 years of life - when illness is likely to be mild. This pattern is also seen in lower socioeconomic groups in the United States. The peak incidence of IM in the United States is between 15 and 19 years of age; the rate in adolescents, 320 to 370 cases per 100 000, is eight times the overall rate of 45 cases per 100000 population. Interestingly, although the incidence in females and males is equal, the peak age incidence in females is 2 years earlier than in males (16 years vs 18 years).
Complications of Infectious Mononucleosis
The communicability of IM is low to moderate, a function of host susceptibility and exposure to virus. Transmission is felt to be through direct and prolonged contact with infected oropharyngeal secretions. Viral shedding in saliva occurs in 90% of patients with IM in the first week of illness and for many months thereafter; 60% to 80% (perhaps 100%) of normal asymptomatic EBV seropositive individuals shed virus intermittently. It is not clear how the frequency and quantity of viral shedding relates to infect i vity.
The incubation period appears to be 30 to 50 days. Most often, the identification of the contact person is not known.
The most common presentation is that of a 3- to 5-day prodrome with malaise, headache, anorexia, and myalgia, followed by the onset of more pronounced symptoms and signs of illness. Fever in the range of 38° to 4O0C, often with chills, is almost always present and may persist for several weeks. Sore throat is a frequent presenting complaint and can be very severe, with exudative pharyngitis in 50% of patients. The lymph node enlargement is characteristically symmetric, posterior cervical (sometimes anterior or generalized) in location, with involved nodes being firm, discrete, and mildly to moderately tender. Clinically apparent splenomegaly may be present in as many as 50% of patients by the second week of illness. Hepatomegaly is not as common as splenomegaly, and jaundice is present in fewer than 10% of patients. Anorexia with nausea and vomiting is also common. Periorbital or facial edema and transient posterior palatal petechiae may each be seen in one third of patients; the palatal petechiae appear in the middle to end of the first week of illness, unlike those caused by the group A, ß-hemolytic streptococcus (GABHS), which are present on the first day of illness. A generalized rash with variable appearances is present in 10% of patients; the eruption may be erythematous, maculopapular, morbilliform, urticarial, or erythema multiforme in nature. If ampicillin is administered to patients with IM, a rash results in approximately 90%. Not all patients have all of the clinical features of classic IM; rather, their signs and symptoms tend to cluster to form particular syndromes. More than 50 years ago, Tidy characterized three clinical forms of IM:
1 . pharyngeal or "anginose,"
2. glandular, and
3. febrile or "typhoidal."
This classification, while simplistic, provides a useful framework for anticipating the clinical course and complications, and for selecting alternative diagnoses that need to be considered.
The pharyngeal or "anginose" presentation is dominated by the exudative tonsillitis with marked pharyngeal edema. The onset tends to be abrupt, fever is high, and the patient often appears toxic. Patients with this form of IM tend to seek medical attention promptly, and the diagnosis, therefore, is usually made early in the course of the illness. Barring complications, the resolution of symptoms tends to be rapid, within 5 to 7 days. Upper airway obstruction due to massive lymphoid hyperplasia and pharyngeal edema is uncommon but occurs and can result in significant morbidity and mortality. The differential diagnosis of this clinical type of IM includes GABHS pharyngitis, which can be distinguished by laboratory tests including rapid antigen detection and throat culture. Notably, GABHS infection and IM frequently occur simultaneously, so the presence of one should not preclude the other from consideration. Mycoplasma and certain viruses are also diagnostic possibilities. Recently, Arcanobacter (formerly Corynebacterium) hemolyticum has been described as a cause of exudative pharyngitis with scarlat iniform rash in adolescents and young adults and thus should be added to the differential diagnosis list. In some cases of IM with severe tonsillopharyngitis, a grayish pseudomembrane forms with friable erythematous mucosa underneath, simulating diphtheria.
Interpretation of Epstein-Barr Virus Serology
The glandular type of IM is characterized by marked lymph node enlargement out of proportion to the pharyngeal involvement. Fever is present, more likely to be low grade and intermittent, and the patient does not look very ill but does have significant malaise. Medical attention is often delayed. The differential diagnosis of this clinical type includes other infections (eg, toxoplasmosis) and conditions that are not as benign as IM (eg, lymphoma, leukemia, and HIV infection).
The febrile or "typhoidal" type of IM is characterized by prolonged fever and malaise without significant pharyngitis; lymphadenopathy is often delayed, appearing 2 to 3 weeks into the illness. Rash may occur at 7 to 10 days. Gastrointestinal symptoms may be pronounced, with anorexia, nausea, and vomiting. The onset is insidious, and, as with the glandular form, the diagnosis may be missed initially or medical attention may be delayed. The clinical features are also seen in infections with cytomegalovirus (CMV), toxoplasmosis, rubella, adenovirus, HHV-6, and HIV, as well as in the namesake, typhoid fever. Symptomatic CMV infection most closely resembles the typhoidal type of IM and accounts for the majority of heterophile antibody- negati ve mononucleosis-like diseases. Hématologie findings include an atypical lymphocytosis; mild hepatitis is also evident chemically, although it is not clinically apparent.
Several nonclassic presentations of IM are worth mentioning, in which the complications of primary EBV infection may be the prominent clinical findings, and the classic clinical findings for IM may be absent or may appear later in the course of illness (Table 1 ). A wide spectrum of neurologic complications in patients with IM have been reported with an estimated frequency of 1% to 2% of patients overall and an incidence among hospitalized patients with IM of 5.5%. Sequelae may be severe, accounting for half of reported fatalities in IM; most deaths have been due to Guillain-Barré syndrome with respiratory failure or meningoencephalitis. However, the overall prognosis for neurologic complications is good, usually with complete resolution.
Thrombocytopenic purpura aiso has been seen to herald IM and is the result of a more severe thrombocytopenia than typically seen with IM. Jaundice rarely may be the presenting sign, representing an unusual degree of severity of the hepatitis of IM with cholestasis.
Splenic rupture is a serious and potentially fatal complication of IM that is estimated to occur in 0. 1 % to 0.2% of cases. Clinical symptoms occur abruptly with pain in the left upper quadrant radiating to the top of the left shoulder (Kehr's sign) and extending to the entire abdomen. Signs and symptoms of hypovolemia develop. A falling hematocrit and a leukocytosis with an absolute neutrophilia are seen. Maki and Reich, in their literature review, found that splenic rupture occurred between the fourth and twenty-first day of symptomatic illness; one half developed during the height of acute illness, the other half in the early convalescent period. Neither the clinical seventy of IM nor the degree of laboratory abnormalities correlated with the susceptibility to splenic rupture. Clinically apparent splenomegaly was reported in less than one half of patients. Although trauma is clearly a risk factor, the majority of splenic ruptures occurred spontaneously without a history of significant strain or trauma.
Multiple other complications have been ascribed to EBV infection. Because of the prominent malaise associated with IM, it was logical to consider a possible relationship between EBV infection and chronic fatigue syndrome. Recent studies have demonstrated EBV not to be the cause of chronic fatigue syndrome.
Hématologie findings are dramatic during the acute phase of illness and are essential for the diagnosis. A modest peripheral blood leukocytosis in the range of 10 000 to 20 OOO/mm1 is found with a lymphocytosis of more than 50% oí the total leukocyte count or more than 4500 /mm}. This is due to EBV activation of B- lymphocytes, which in turn causes a proliferation of T- lymphocytes. Atypical lymphocytes, also called "Downey" cells, constitute more than 10% of the total leukocyte count, or more than 1000/mmA These cells are either EBV-transfbrmed B-lymphocytes or, more commonly, activated suppressor/cytotoxic (CDS) Tlymphocytes. They vary in size but tend to be large, have vacuolated basophilic cytoplasm, and are noted on the blood smear to be indented by neighboring erythrocytes. Atypical lymphocytes are also seen in other viral infections eg, CMV, HIV, hepatitis, rubella, rubeola, and mumps) and in toxoplasmosis but comprise less than 10% of the total leukocyte count with the exceptions of CMV infection and toxoplasmosis.
During the second week of acute illness, a neutropenia of <2000/mm5 may be present but generally is not severe with return to normal after the acute illness resolves. Should a marked neutrophilia be present, a complication such as splenic rupture or secondary bacterial infection should be suspected or an alternative diagnosis considered.
A mild reduction of the platelet count, in the range of 100000 to 140000/mm3, may be present in as many as 50% of patients; abnormalities in platelet function also can be demonstrated. Anemia usually is not a feature; its presence, therefore, should raise suspicion of complications such as splenic rupture or autoimmune hemolysis.
Chemical evidence of a mild hepatitis is present in approximately 90% of patients with IM, peaking in the second to third week of illness. Aminotransferases (transaminases), alkaline phosphatase, and LDH concentrations are elevated twofold to threefold. Serum bilirubin is generally only mildly elevated, in the 1 to 3 mg/dL range, and jaundice is not clinically apparent in 90% of patients. If liver chemistries are normal, one should reconsider the diagnosis of primary EBV infection.
The diagnosis of IM is suggested by the characteristic clinical and hématologie findings and confirmed by serologie studies. The classic test for IM is the demonstration of heterophile antibody (HA). HAs are IgM -antibodies, termed "heterophile" because they are directed against phylogenetically unrelated antigens: eg, human antibody against sheep red blood cells. Heterophile antibodies are induced in a variety of malignant states, in serum sickness, and by a number of viruses. The HAs produced by patients with IM are distinguished by their reaction with cells of different species: they agglutinate sheep and horse RBCs after preabsorption with guinea pig kidney, but not after preabsorption with bovine RBCs. (The HAs of patients with IM cause bovine RBCs to hemolyze.) This differential response is the basis of current HA screening tests for IM, eg, the Monospot and other slide and card tests that are used in office and clinical laboratories. These tests are simple, rapid, and relatively inexpensive.
HAs appear several days into the illness. They are present in approximately 70% of patients with IM during the first week, and in 85% to 95% by the third week. Therefore, if it is early in the course and the differential HA test is negative, it is reasonable to wait a week and repeat the study. If after one week the study is still negative, and the clinical pictute and hématologie data continue to suggest IM, the clinician should determine whether the result is a true negative (ie, the patient has an alternative diagnosis, such as CMV infection) or a false negative, in which case serologie evidence of primary EBV infection should be sought.
A variety of EBV structural and nonstructural antigens and corresponding antibodies have been identified. The pattern of antibody responses is most useful for the practitioner in sorting out HA-negative mononucleosis-like disease. Viral capsid antigens (VCA) are found within host cells with actively replicating virus. Serum IgM and IgG to EBV-VCA are seen in the acute phase of EBV infection. VCAIgM response is immediate but transient, lasting only 1 to 2 months. VCA-IgG response is early and persists lifelong. Early antigens (EA) are nonstructural proteins synthesized when latently infected cells are stimulated to teplicate virus. Two components of EA are defined by immunofluorescent staining distribution in cells: diffuse (D) and restricted (R). In most patients with IM, the antibody response is directed to the D-component. The EA-IgG response peaks 3 to 4 weeks after onset of symptoms and generally persists for several months. Therefore, it can be considered as a marker for acute or recent infection. Epstein-Barr nuclear antigens (EBNA) are expressed by B-cells that harbor the EBV genome. IgG antibodies to EBNA develop later, several weeks to months after clinical onset of IM, and persist for life. Primary infection with EBV is confirmed when a serum specimen collected within 4 weeks after the clinical onset of IM contains VCA-IgM, VCA-IgG, and EA-D. The presence of VCA-IgM alone can make the diagnosis, but the test is not perfect: not all patients have positive tests, and false-positive tests can occur if rheumatoid factor is present in the serum. Because of the limitations of the standard immunofluorescent antibody tests, there has been considerable interest in the past few years in using newer technologies, such as enzyme-linked immunosorbant assay, and in investigating other markers of EBV infection (such as IgM EBNA).
RETURN TO ACTIVITIES
Once the diagnosis of IM is made, the physician must counsel patients as to the expected period of incapacitation. In general, acute symptoms of IM pass in 1 to 2 weeks, with resolution of fatigue in 2 to 4 weeks, although the recovery period may be more rapid or more prolonged. The number of days from onset of symptoms to diagnosis has been shown to be a statistically significant predictor of the duration of IM. (Time of diagnosis is defined as the date of the first positive heterophile test.) When the onset of symptoms is abrupt, as in the pharyngeal presentation, diagnosis is usually made quickly, and the recovery period is short (fewer than 10 days). With a more insidious onset of disease, as might be seen with the glandular or typhoidal presentation, the diagnosis is often delayed. This delay in diagnosis may be due to the patient not feeling sufficiently ill to seek medical care, to misdiagnosis, or to delayed heterophile antibody response. The prominence of gastrointestinal symptoms, such as anorexia, nausea, or vomiting, at the time of diagnosis may imply a prolonged convalescence; no other symptoms have been shown to have any predictive significance.
During the acute phase of illness with fever, pharyngitis, significant malaise, and myalgia, activity should be limited to what the patient can tolerate; strict bedrest is not required. As the patient's sense of well-being increases, generally within 1 week, there should be a gradual return to daily activities including school, but rigorous activity and athletic training should be excluded.
The exception to the above pertains to patients with obvious splenomegaly or splenic discomfort, for whom it is more prudent to advise restricted activity, with walking kept to a minimum, until splenic enlargement regresses. Some clinicians even advise stool softeners for these patients to prevent straining with bowel movements.
The following guidelines for resumption of athletic activity are adapted from Maki and Reich: 1) In patients with clinically enlarged or tender spleens, most activity and all athletics should be restricted until splenomegaly and splenic discomfort have totally resolved. 2) For patients not involved in strenuous activity or contact sports, light, nonimpact activity (eg, swimming) can be resumed after 21 days of illness if the patient subjectively feels ready. (Note that contact sports in this context includes activities in which there is likely to be contact with the abdomen, such as the uneven bars in gymnastics, as well as the traditional contact sports, such as football and basketball.) Generally, full participation can be resumed 1 month after onset of symptoms. 3) For patients involved in strenuous training or contact sports, early easy training is allowable, as their energy level permits, but a return to full exercise and contact participation should be delayed at least 4 to 6 weeks. Because splenic enlargement is not appreciated by palpation 50% of the time, it is reasonable to assess the size of the spleen in these athletes by ultrasound; if splenomegaly is present, follow-up ultrasonography should be performed at 1- to 2-week intervals, with return to full activity deferred until splenomegaly resolves.
Splenic rupture, although the most dramatic, is not the only consideration in making guidelines for resumption of athletic activities. Loss of performance with a variety of viral infections is well-documented and may be due to skeletal muscle dysfunction. With loss of performance, the risk of injury increases.
Providing supportive therapy, with appropriate guidelines for activity, is the mainstay of medical management. Patients at tisk for or with complications should be identified promptly so that treatment options can be considered early. Analgesia is very important both for sore throat pain and other associated symptoms including headache and myalgia. Adequate analgesia for those with odynophagia may prevent dehydration and obviate the need for hospitalisation and intravenous fluids. Acetaminophen is preferable to aspirin since aspirin inhibits platelet function, which may already be present to some degree in IM. If stronger analgesia is needed, codeine is useful, particularly when combined with acetaminophen.
The role of steroids in the treatment of IM has been controversial for many years. The specific indication for which there is documented usefulness with little controversy is upper airway obstruction. Steroids have a dramatic effect in reducing the edema and hyperplasia of lymphoid tissue in the naso-oropharynx, relieving obstruction and respiratory distress. Surgical intervention tonsillectomy or tracheostomy) may be avoided if steroids are administered when moderate distress is evident. Candidates for steroid therapy are those with severe odynophagia, shortness of breath, retractions, or inspiratory stridor in the supine position. After initiation of intravenous corticosteroids, striking improvement is seen within 6 to 24 hours.
Corticosteroids also may be helpful in other complications of IM (based on anecdotal reports, not controlled studies) including neurologic, hématologie (hemolytic anemia, thrombocytopenia, granulocytopenia, and DIC), and cardiac (myocarditis) complications. There is no evidence that corticosteroids affect splenomegaly or reduce the risk of splenic rupture.
The value of corticosteroids in uncomplicated cases of IM to shorten the duration of fever and disability has not been proved by well-designed studies. Several reports suggest a significant decline in fever and improved (subjective) sense of well-being. There are theoretical causes for concern, however. For example, in other forms of viral hepatitis, steroids produce a "biochemical whitewash," with initial improvement of laboratory tests at the expense of clinical healing; host factors responsible for limiting the virus appear to be depressed by corticosteroids. Moreover, EBV persists in the host and is capable of producing immune dysfunction; whether the administration of steroids might adversely afïéct immune function, short- or long-term, is not known. For these reasons, the routine use of steroids in uncomplicated IM is not recommended.
Acyclovir is a nucleoside analog with good in vitro antiviral activity against EBV. A placebo-controlled, double-blind study has been conducted to determine whether IV acyclovir could be used to reduced clinical symptoms in patients with IM by decreasing B-cell activated immune response. There were no significant differences in individual symptoms or laboratory parameters, but the overall subjective patient score showed faster improvement in the acyclovir treated group. More data are needed before any recommendations for use of acyclovir can be made.
Infectious mononucleosis is a clinical manifestation of primary EBV infection in adolescents, characterized by a triad of clinical, laboratory, and serologie features. The classic signs and symptoms are not seen in every patient; rather, the presentations tend to fit into one of three clinical forms (pharyngeal, glandular, or febrile). Recognizing these syndromes provides a useful framework for anticipating the clinical course, complications, and differential diagnosis. Nonclassic presentations of IM include a wide variety of neurologic abnormalities, thro mboc y topen ic purpura, and splenic rupture. The laboratory features of IM include absolute lymphocytosis with a large percentage of atypical lymphocytes, and abnormal liver chemistries in 90% of patients. The diagnosis of IM is confirmed serologically, usually with the demonstration of heterophile antibodies; the test can conveniently be performed in office laboratories. If the heterophile antibody test is negative, EBV-specific serologie tests can identify whether the illness is due to primary EBV infection. Once the diagnosis of IM is made, appropriate guidelines for resumption of activity should be provided to patients, especially to those with evidence of splenomegaly. Medical management includes supportive therapy with adequate analgesia. Corticosteroids are indicated for patients with upper airway obstruction; they may be helpful in patients with neurologic, hématologie, or cardiac complications. Acyclovir may prove to be useful, but further studies are needed before its use can be recommended.
The authors thank Drs Sarah Cheeseman and Jerry Durbin for their counsel and Drs Evan Charney, Jerry Durbin, and Sharon Swindell for their review of the manuscript.
Differential Diagnosis and Complications
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Prognosis and Management
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Cheeseman SH. Infetiious raononucleosis. Semai Hemalul. 19S8;25:261-268. A readable concise revient. Referí io ine three faescraaaiira of IM os deuTibed by Tidy m Lancet 1934;2J80-J86. Staat' of àie iifmiigicai uspícls o/ EBV con bf ftnmd m ine same unie o/SeminHematol. l9Sfi.25:2-Ì7-280.
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Complications of Infectious Mononucleosis
Interpretation of Epstein-Barr Virus Serology