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  • Ticket #10533 – Description

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    10 <p> <p> Infectious mononucleosis (IM), commonly known as <em>kissing disease,</em> is a viral syndrome resulting from an acute infection with Epstein-Barr virus (EBV). Mononucleosis typically occurs between early childhood and early adulthood and is ordinarily self-limiting as the patient develops EBV-specific immunity; in some cases, however, IM can lead to severe complications.<sup>1-4</sup></p> <p> Worldwide, the EBV may be present in 95% of adults between 35 and 40.<sup>2,5,6</sup> In patients previously infected during early adulthood, the EBV remains dormant in the B-lymphocytes, and those affected may continue to carry asymptomatic infection lifelong.<sup>1,7</sup></p> <p> <strong>Epidemiology<br /> </strong>IM antibodies may be present in 90% to 95% of the population; however, epidemiologic data regarding infection vary among age-groups and by geographic location.<sup>2,4</sup> IM occurring in patients between ages 1 and 5 years is very limited in industrialized countries and within higher socioeconomic groups; in these settings, infection onset occurs primarily in the second decade of life. EBV is rarely found in patients younger than 1 year, possibly because of serologic protection from maternal antibodies.<sup>6</sup></p> <p> Early childhood infection with EBV is predominantly found in the developing countries and in lower socioeconomic groups. EBV infection in young children usually presents with nonspecific symptoms. Wherever improvements in hygiene have been made during recent years, EBV infection in early childhood has become increasingly rare.<sup>5,8</sup></p> <p> Susceptibility to EBV becomes more pronounced during adolescence and early adulthood; in the United States, the incidence of IM is 500 cases per 100,000 persons per year, with persons between ages 15 and 24 accounting for the greatest incidence.<sup>5</sup> Among college freshmen who are initially seronegative for EBV (estimates range from 30% to 70%), between 10% and 20% will become infected with the virus; of these, 30% to 50% will develop IM. IM is not seasonal or cyclical and has no sexual predisposition.<sup>5,8,9</sup></p> <p> <strong>Pathophysiology<br /> </strong>EBV, a gamma herpesvirus, is spread via intimate contact from persons recently infected with EBV infection to other susceptible humans.<sup>5</sup> EBV is typically transmitted through oropharyngeal secretions, mainly saliva. After its transmission, the EBV enters epithelial B-lymphocytes, which contain receptors for EBV. Infected B-lymphocytes target the salivary glands, the lymphoid cells, and the oropharynx, causing pharyngitis and other early manifestations of IM. After infection, the host immune response is an activation of T cells against infected B cells, producing larger, atypical lymphocytes called <em>Downey cells.</em><sup>10</sup></p> <p> The infected B cells then enter the blood stream, carrying the virus throughout the body to the spleen, liver, and peripheral lymph nodes. The spread of these infected lymphocytes elicits a significant cellular immunologic response to the viral infection. This immunologic response is largely responsible for the clinical presentation of IM in the lymph nodes, spleen, and possibly the liver.<sup>10</sup></p> <p> Once acute infection occurs, antibodies are produced against both EBV and unrelated viral species. Recent-onset infection produces heterophile antibodies, the presence of which is helpful in the diagnosis of IM. Specific antibodies to the EBV also develop, including immunoglobulin G (IgG) and IgM; these and others can be useful for serologic identification of EBV. Once an individual is acutely infected with EBV, he or she becomes a lifelong carrier of the virus.<sup>10</sup></p> <p> The incubation period of the EBV is between 30 and 50 days,<sup>5,10</sup> making it difficult to pinpoint an exact date of exposure. Transmission of the virus to others may be possible for three months or longer; even after symptoms are resolved, the virus is shed in the saliva for months. Additionally, the EBV has been found in semen and cervical secretions, indicating the possibility of sexual transmission.<sup>5,9,10,11</sup></p> <p> <strong>Clinical Manifestations<br /> </strong>Patients with IM usually seek medical treatment for worsening sore throat and increasing fever. The clinical presentation of IM can vary, depending on time between symptom onset and that of presentation.<sup>4</sup> However, the triad of most common clinical symptoms, which ordinarily resolve in one to three weeks, are sore throat, fever, and lymphadenopathy.<sup>5,10</sup> During the one- or two-week-long prodromal period, patients may also have nonspecific symptoms of malaise, fatigue, and myalgia. About half of patients report headache.<sup>10,12</sup></p> <p> <strong>Triad of Common Symptoms<br /> </strong><em>Pharyngitis,</em>the most prominent physical finding, can be severe. It presents in the initial weeks of illness, with pharyngeal exudates present in about half of cases.<sup>10,13</sup> The pharyngeal exudates in IM may be difficult to distinguish from those associated with streptococcal pharyngitis. With inflammation of the lymphoid tissue, tonsillitis develops; tonsillar ulceration has been reported in 20% of patients with IM.<sup>13</sup> “Kissing tonsils,” with enlargement of the tonsillar pillars causing the tonsils to touch, can lead to airway compromise.<sup>14</sup> In addition to pharyngitis and tonsillitis, oral palatal petechiae may develop.<sup>5,8,10</sup></p> <p> Low-grade <em>fever,</em> rarely exceeding 102°F, usually lasts for one to two weeks but may persist for as long as five weeks.<sup>11</sup></p> <p> Cervical <em>lymphadenopathy</em> usually presents with symmetrically enlarged, firm, mobile and tender anterior and posterior lymph nodes, as well as the submandibular lymph nodes; however, clinicians should be aware that more generalized adenopathy may be present, affecting the axillary and inguinal nodes.<sup>2,10,11</sup> Lymphadenopathy usually resolves within one to two weeks.</p> <p> <strong>Additional Manifestations of IM<br /> </strong>Skin rashes have been reported in 3% to 15% of patients with IM,5 although results from a recent retrospective study suggest that one-third of patients with IM who are initially treated with amoxicillin experience rash.<sup>15</sup> This maculopapular, pruritic, copper-colored or tan and brown rash usually begins about 5 to 10 days after antibiotic therapy is initiated. The rash, which is not considered an allergic reaction, usually resolves once the antibiotic is discontinued.<sup>10,12,16</sup></p> <p> Hepatosplenomegaly, particularly splenomegaly, is common—although this is usually a late finding in patients with IM, developing during the second to third week of illness.<sup>11,12,16</sup> Abdominal pain is typically absent. However, when patients complain of severe left upper quadrant abdominal pain, splenic ultrasound should be considered to assess for splenic enlargement or possible rupture.<sup>8</sup></p> <p> <strong>Differential Diagnosis<br /> </strong>Not all patients with symptoms suggestive of IM are found to be infected with EBV. Other pathogens may be responsible for primary infection in these patients10 (see Table 1<sup>5,10,12,17-20</sup>).</p> <p style="text-align: center;"> <img alt="" src="/UserFiles/JUN13_CE_T1.jpg" style="width: 360px; height: 839px;" /></p> <p> <em>Streptococcal pharyngitis</em>is the illness most likely to be confused with IM because of the similarity of symptoms; one in four children with acute sore throat (as well as 5% to 20% of affected adults) may be infected with group A beta-hemolytic streptococcus (GABHS).<sup>17-19</sup> Although, in addition to sore throat, patients with GABHS may experience localized swelling of the anterior cervical lymph nodes, GABHS is not usually characterized by posterior cervical lymphadenopathy. Additionally, the hepatosplenomegaly and fatigue common to IM would not be present in patients with streptococcal pharyngitis.<sup>5</sup></p> <p> GABHS is confirmed by a positive throat culture for group A streptococcus<sup>17</sup>; in patients with negative results on a rapid antigen test, IM should be considered in the differential diagnosis.</p> <p> <em>Toxoplasmosis</em>can manifest with symptoms similar to those of EBV-associated IM. The classic IM symptoms of hepatosplenomegaly and pharyngitis are not often seen in cases of toxoplasmosis, however. The history should reveal contact with cat droppings or cat litter.<sup>12,20</sup></p> <p> Patients infected with <em>cytomegalovirus</em> (CMV) can present asymptomatically or with the common triad of symptoms of IM. Splenomegaly, malaise, and lymphadenopathy may be present. A diagnosis of CMV is confirmed by the presence of antibodies to serum CMV IgM.<sup>12,20</sup></p> <p> <em>Adenovirus</em>typically manifests with cold-like symptoms, cough, conjunctivitis, and diarrhea. The triad of symptoms typically seen with IM may be present with decreased severity in patients with adenovirus. Culture of nasopharyngeal swabbings can confirm a diagnosis of adenovirus.<sup>12,20</sup></p> <p> Symptoms of <em>rubella</em> can mimic those of IM, but the classic rubella rash should be a distinguishing factor. Lymphadenopathy most commonly affects the postauricular and occipital nodes. Parents may acknowledge that the patient has not been immunized against rubella.<sup>12</sup></p> <p> Manifestations of <em>hepatitis A</em> include hepatomegaly, fever, jaundice, abdominal pain, and fatigue. Symptoms associated with IM, including periorbital edema, pharyngitis, splenomegaly, and adenopathy, are not typically seen in patients with hepatitis A. Laboratory findings in the patient with hepatitis would include elevations in alanine aminotransferase and aspartate aminotransferase. Serology would be positive for hepatitis A virus antibody IgM and negative for EBV heterophile antibodies.<sup>12,16</sup></p> <p> <em>Herpes simplex virus,</em>commonly known as a cold sore, manifests with pharyngitis with exudate, gingivostomatitis, and odynophagia (painful swallowing). The appropriate polymerase chain reaction (PCR) test can be used to confirm the presence of herpes virus.<sup>12,20</sup></p> <p> <em>HIV</em>screening should be conducted in at-risk patients, as IM and HIV can present with similar symptoms of fever, malaise, lymphadenopathy, and rashes, especially in the early phase of primary HIV infection. Pharyngitis is less common in patients with HIV infection than in those affected by IM; rather, mucocutaneous lesions and gastrointestinal symptoms, such as diarrhea, are likely to be present.<sup>5</sup> Diagnostic findings include a positive ELISA HIV antibody test and positive plasma viral load.<sup>12,20</sup></p> <p> <strong>Diagnosis<br /> </strong>Pertinent information elicited in the patient history should include signs and symptoms, particularly the common triad of pharyngitis, fever, and lymphadenopathy, and possible exposure or sick contacts. Certainly, patients with symptoms of pharyngitis and continued fatigue that are unresolved within 48 to 72 hours should be screened for IM.<sup>12,13</sup></p> <p> In addition to the in-depth history, routine hematologic testing is conducted, as well as serologic testing to confirm the diagnosis. A complete blood count will reveal hyperlymphocytosis (≥ 50%), an elevated white blood cell count (usually ranging from 10,000 to 20,000/mL in most patients), and at least 10% atypical lymphocytes.<sup>2,6,8,11</sup> Elevations in liver enzymes are found in 80% to 90% of cases.<sup>2,11</sup></p> <p> <strong>Heterophile Antibody Testing<br /> </strong>In the symptomatic patient, a positive result on the <em>monospot,</em> a rapid test for heterophile antibodies, is 85% sensitive and 94% specific for IM.<sup>5,6,8</sup> Heterophile serology is elevated for the first four weeks of infection, then declines rapidly; thus, this test should not be used beyond one month of symptom onset. Additionally, false-negative monospot test results have been reported in about one-fourth of patients during the first week of symptoms.<sup>5,6</sup> For that reason, when suspicion for IM is high but the monospot yields negative results, additional serology with greater sensitivity and specificity is warranted.</p> <p> Of note, false-negative results on heterophile serology are common in children younger than 12.<sup>11,21</sup></p> <p> <strong>EBV Serology<br /> </strong>Because IM represents infection with EBV, serologic testing for EBV is accurate, highly specific, and recommended for use when IM is strongly suspected, particularly in infants and younger children. Serologic tests are more reliable, though more expensive and time-consuming, than heterophile antibody testing.<sup>11,22</sup></p> <p> Various EBV serologic tests are used for diagnosis, and it is recommended by the CDC6 that these tests be performed concurrently because the antibody response in EBV is rapid. A blood sample obtained during the acute phase of illness will reveal antibodies representing acute, recent, past, or reactive disease.<sup>6</sup></p> <p> Testing for EBV-specific IgM and IgG antibodies against viral capsid antigen (VCA), early antigen (EA), and the Epstein-Barr virus nuclear antigen proteins (EBNA) is 97% sensitive and 94% specific for a diagnosis of IM.<sup>5,11,23</sup> EBV antigen testing can be performed using the following laboratory tests: IgM VCA, IgG VCA, EA IgM, and EBNA IgG. The decision to perform antigen testing is based on timing and onset of symptoms (see Table 2<sup>5,11</sup> for possible findings from certain tests). Primary EBV infection is indicated by the presence of IgG antibodies against VCA or of IgM antibodies against VCA, <em>in addition to the absence of</em> EBNA antibodies.<sup>6,23</sup></p> <p style="text-align: center;"> <sup><img alt="" src="/UserFiles/JUN13_CE_T2.jpg" style="width: 360px; height: 705px;" /></sup></p> <p> As with any laboratory testing, the EBV serology should be correlated with patient presentation and the overall clinical picture. Early antigen testing, it should be noted, is often recommended for patients who have significant and persistent symptoms of IM but who are past the four-week time frame in which heterophile antibody testing is effective.<sup>11</sup></p> <p> A quantitative real-time PCR assay, which detects EBV viral load, can also be used to test blood or plasma for acute infection.<sup>11</sup> PCR testing is usually reserved for young children with significant symptoms but negative results on the monospot test; or for patients presenting with IM-like symptoms but having more complex conditions, such as HIV, in which further differentiation of EBV DNA subtypes is needed.<sup>24,25</sup></p> <p> <strong>Considerations in Specific Patient Populations<br /> </strong><em>Adolescents and young adults.</em>When caring for adolescents and young adults, clinicians are advised to obtain an in-depth sexual history. In patients who are considered at high risk for sexually transmitted diseases (STDs), testing for HIV and other STDs is also recommended.<sup>26</sup></p> <p> <em>Adults and elderly adults.</em>Epidemiology does not support the likelihood of IM in these age-groups; this can lead to a missed diagnosis or a misdiagnosis with one of the more common adult infectious diseases, including those of a hepatic or hematologic nature.<sup>27</sup> Adults older than 40 account for 7.5% of cases of IM.<sup>28</sup></p> <p> In these patients, manifestation of the clinical signs of IM may be altered. Rather than displaying the classic triad of symptoms, older patients may present with nonspecific complaints of fever, myalgias, malaise, and fatigue.<sup>16,28</sup> Serologic testing should be considered to avoid misdiagnosis in this age-group.</p> <p> <strong>Complications<br /> </strong>Most patients with IM recover and are able to return to normal activity within two to three months.<sup>5</sup> Several complications can develop, however (see Table 3<sup>3,5,10,12,14,29,30</sup>).</p> <p style="text-align: center;"> <img alt="" src="/UserFiles/JUN13_CE_T3.jpg" style="width: 360px; height: 839px;" /></p> <p> Chronic fatigue is the most commonly reported sequela of IM. In one study of 12- to 18-year-olds who had had IM, chronic fatigue was reported in 13%, 7%, and 4% of patients at six, 12, and 24 months, respectively.<sup>29</sup> The study authors concluded that IM during adolescence may be a risk factor for chronic fatigue syndrome.</p> <p> A more serious but less common complication of IM is upper airway obstruction, occurring in perhaps 1% to 5% of patients.<sup>5,10</sup> The result of IM-associated tonsillar enlargement and edema in the pharyngeal tissue, upper airway obstruction can require hospitalization. Appropriate interventions include IV corticosteroids, tonsilloadenoidectomy, and endotracheal intubation.<sup>10,14</sup></p> <p> Also less common but extremely serious is splenic rupture, which develops in 0.5% to 1% of patients with IM.<sup>5</sup> Affected patients usually require emergency surgery.<sup>8,12</sup></p> <p> Unusual complications include central nervous system effects, such as meningitis, Guillain-Barré syndrome, encephalitis, Bell’s palsy, optic neuritis, perceptual distortions, and mental status changes. Other neurologic abnormalities, such as cerebellar ataxia and demyelinating diseases, have been reported.<sup>10,14</sup> Ocular manifestations sometimes associated with IM are periorbital edema, dry eyes, keratitis, uveitis, and conjunctivitis.<sup>5,16</sup></p> <p> On occasion, clinicians may see patients with IM complicated by respiratory involvement, such as mediastinal lymphadenopathy, interstitial pneumonitis, myocarditis, and plural effusion. Incidences of respiratory failure and pneumonia have been documented, primarily in immunocompromised patients.<sup>3,10</sup></p> <p> Potential hematologic complications of IM include hemolytic anemia, thrombocytopenia, and mild neutropenia.<sup>10,11</sup> Although these conditions have been reported in 25% to 50% of patients with IM, they typically present in a mild form and resolve within a few weeks.<sup>5,10</sup></p> <p> Another serious complication of IM, though rare, is chronic active EBV infection, a persistent syndrome with manifestations that may include fever, significant lymphadenopathy, persistent hepatitis, and a high viral load in the peripheral blood.<sup>3,30</sup></p> <p> If symptoms of IM persist for longer than 6 months, further evaluation should take place, including investigation for other chronic disease states, such as HIV, lupus erythematosus, or chronic fatigue syndrome.</p> <p> The most common complication of IM misdiagnosed as GABHS is a rash resulting from treatment with penicillin (which is an appropriate treatment for GABHS but not IM).<sup>15</sup> Although penicillin use is the most common cause of drug-induced rash in patients with IM, extremely rare cases have been reported in which a rash developed after treatment with a macrolide, specifically azithromycin.<sup>31</sup></p> <p> <strong>Management of IM<br /> </strong>The goals of therapy are to minimize complications and restore the patient to full capacity. Supportive care is the mainstay, including bed rest, fluids, and administration of NSAIDs.</p> <p> Although the incidence of splenic rupture is 0.5% to 1%,<sup>5</sup> activity should be restricted to minimize the risk. Patients are usually advised to restrict activity (especially contact sports) for at least three to four weeks. Strenuous activity should be avoided for three weeks to two months.<sup>8,32</sup></p> <p> A scaffold plan to return to full activity after week 4 should be provided to asymptomatic patients who receive adequate hydration and are unaffected by splenomegaly.<sup>32,33</sup> If patients experience respiratory involvement related to tonsillar enlargement and tissue hypertrophy causing increased respiratory obstruction, oral corticosteroids can be used.</p> <p> Corticosteroids are also appropriate for hematologic complications such as hemolytic anemia and thrombocytopenia. Other than these or respiratory complications, there is insufficient evidence for corticosteroid use as supportive treatment for IM.<sup>34</sup> Similarly, data to support the use of antivirals, such as acyclovir, are inconclusive.<sup>35</sup></p> <p> <strong>Patient Education<br /> </strong>Patients should be educated about progression of the disease as well as the timing and length of expected clinical symptoms during the disease course. Patients infected with IM do not need to be isolated but should avoid exposing others to infected oropharyngeal secretions by kissing or sexual contact.<sup>5,11</sup> Patients should avoid sharing items that may harbor the EBV, such as drinking containers or eating utensils, particularly during the febrile period.</p> <p> Individuals must also be advised to curtail active physical activities, specifically strenuous or contact sports, until given clearance by their provider.<sup>8</sup></p> <p> <strong>Conclusion<br /> </strong>Once a patient is infected with EBV, the virus remains present for life. EBV infection is dormant in the B-lymphocytes and can occasionally become reactivated. In these cases, the patient becomes infectious, though rarely displaying symptoms of latent B-lymphocyte infection. In certain circumstances, given the right environment in susceptible contacts, the reactivated virus may produce subclinical symptoms, and the virus can be spread to others.</p> <p> <strong>References<br /> </strong>1. Jain N, Bhatia V, Lattoo S. Epstein-Barr virus and associated head and neck manifestations. <em>Ann Nigerian Med.</em> 2011;5:38-41.</p> <p> 2. World Health Organization, Initiative for Vaccine Research. Viral cancers. www.who.int/vaccine_research/diseases/viral_cancers/en/index1.html. Accessed May 8, 2013.</p> <p> 3. Joo EJ, Ha YE, Jung DS, et al. An adult case of chronic active Epstein-Barr virus infection with interstitial pneumonitis. <em>Korean J Intern Med.</em> 2011;26:466-469.</p> <p> 4. Çeltik C, Küçükugurluoglu Y, Balci DB, et al. Evaluation of clinical and laboratory features of Epstein-Barr virus–associated acute infectious mononucleosis in children. <em>Trakya Universitesi Tip Fakultesi Dergisi.</em> 2008;25:221-227.</p> <p> 5. Luzuriaga K, Sullivan JL. Infectious mononucleosis. <em>N Engl J Med.</em> 2010;362:1993-2000.</p> <p> 6. CDC. Epstein-Barr virus and mononucleosis (2006). www.CDC.gov/ncidod/diseases/ebv.htm. Accessed May 8, 2013.</p> <p> 7. Macsween KF, Higgins CD, McAulay KA, et al. Infectious mononucleosis in university students in the United Kingdom: evaluation of the clinical features and consequences of the disease. <em>Clin infect Dis.</em> 2010;50:699-706.</p> <p> 8. Bennett NJ. Pediatric mononucleosis and Epstein-Barr virus infection (2012). http://emedicine.medscape.com/article/963894. Accessed May 8, 2013.</p> <p> 9. Crawford DH, Macsween KF, Higgins CD, et al. A cohort study among university students: identification of risk factors for Epstein-Barr virus seroconversion and infectious mononucleosis. <em>Clin Infect Dis.</em> 2006;43:276-82.</p> <p> 10. Jenson HB. Epstein-Barr virus. <em>Pediatr Rev.</em> 2011;32:375-384.</p> <p> 11. Valachis A, Kofteridis DP. Mononucleosis and Epstein-Barr virus infection: treatment and medication. Virus Adaptation Treatment. 2012; 4:23-28. www.dovepress.com/getfile.php?fileID=12299. Accessed May 8, 2013.</p> <p> 12. Marshall BC, Foxworth MK II. Epstein-Barr virus–associated infectious mononucleosis (2012). <em>Contemp Pediatr.</em> http://digital.health caregroup.advanstar.com/nxtbooks/advanstar/cntped_201210/index.php?start id=52. Accessed May 8, 2013.</p> <p> 13. Kutuya N, Kurosaki Y, Suzuki K, et al. Pharynigitis of infectious mononucleosis: computed tomography findings. <em>Radiat Med.</em> 2008;26:248-251.</p> <p> 14. Kakani S. Airway compromise in infectious mononucleosis: a case report. <em>Cases J.</em> 2009;2;6736.</p> <p> 15. Chovel-Sella A, Ben Tov A, Lahav E, et al. Incidence of rash after amoxicillin treatment in children with infectious mononucleosis. <em>Pediatrics.</em> 2013 Apr 15. [Epub ahead of print]</p> <p> 16. Cunha BA. Infectious mononucleosis (2013). http://emedicine.medscape.com/article/222040-overview. Accessed May 8, 2013.</p> <p> 17. Choby BA. Diagnosis and treatment of streptococcal pharyngitis. <em>Am Fam Physician.</em> 2009;79:383-390.</p> <p> 18. Bisno AL, Gerber MA, Gwaltney JM Jr, et al; Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis. <em>Clin Infect Dis.</em> 2002;35:113-125.</p> <p> 19. Danchin MH, Rogers S, Kelpie L, et al. Burden of acute sore throat and group A streptococcal pharyngitis in school-aged children and their families in Australia. <em>Pediatrics.</em> 2007;120:950-957.</p> <p> 20. Hurt C, Tammaro D. Diagnostic evaluation of mononucleosis-like illnesses. <em>Am J Med.</em> 2007;120;911.e1-e8.</p> <p> 21. Dohno S, Maeda A, Ishiura Y, et al. Diagnosis of infectious mononucleosis caused by Epstein-Barr virus in infants. <em>Pediatr Int.</em> 2010;52:536-540.</p> <p> 22. Tamaro G, Donato M, Princi T, Parco S. Correlation between the immunological condition and the results of immunoenzymatic tests in diagnosing infectious mononucleosis. <em>Acta Biomed.</em> 2009;80:47-50.</p> <p> 23. de Ory F, Guisasola ME, Sanz JC, García-Bermejo I. Evaluation of four commercial systems for the diagnosis of Epstein-Barr virus primary infections. <em>Clin Vaccine Immunol.</em> 2011;18:444-448.</p> <p> 24. Kimura H, Ito Y, Suzuki R, Nishiyama Y. Measuring Epstein-Barr virus (EBV) load: the significance and application for each EBV-associated disease. <em>Rev Med Virol.</em> 2008;18:305-319.</p> <p> 25. Gatto F, Cassina G, Broccolo F, et al. A multiplex calibrated real-time PCR assay for quantitation of DNA of EBV-1 and 2. <em>J Virol Methods.</em> 2011;178:98-105.</p> <p> 26. Simpson T, Ivey J. Fever and sore throat in a 16-year-old female. <em>Pediatr Nurs.</em> 2007;33:245-246.</p> <p> 27. Malfuson JV, Dutasta F, Konopacki J, et al. Infectious mononucleosis and monoclonal B lymphocytosis in an elderly man. <em>J Am Geriatr Soc.</em> 2011;59:2156-2157.</p> <p> 28. Dourakis SP, Alexopoulou A, Stamoulis N, et al. Acute Epstein-Barr virus infection in two elderly individuals. <em>Age Ageing.</em> 2006;35:196-198.</p> <p> 29. Katz BZ, Shiraishi Y, Mears CJ, et al. Chronic fatigue syndrome after infectious mononucleosis in adolescents. <em>Pediatrics.</em> 2009;124:189-193.</p> <p> 30. Okano M, Kawa K, Kimura H, et al. Proposed guidelines for diagnosing chronic active Epstein-Barr virus infection. <em>Am J Hematol.</em> 2005;80:64-69.</p> <p> 31. Dakdouki GK, Obeid KH, Kanj SS. Azithromycin-induced rash in infectious mononucleosis. <em>Scand J Infect Dis.</em> 2002;34:939-941.</p> <p> 32. Waninger KN, Harcke HT. Determination of safe return to play for athletes recovering from infectious mononucleosis: a review of the literature. <em>Clin J Sport Med.</em> 2005;15:410-416.</p> <p> 33. Hosey RG, Rodenberg RE. Infectious disease and the collegiate athlete. <em>Clin Sports Med.</em> 2007;26:449-471.</p> <p> 34. Candy B, Hotopf M. Steroids for symptom control in infectious mononucleosis. <em>Cochrane Database Syst Rev.</em> 2006;(3):CD004402.</p> <p> 35. Torre D, Tambini R. Acyclovir for treatment of infectious mononucleosis: a meta-analysis. <em>Scand J Infect Dis.</em> 1999;31:543-547.</p></p>
     10<p> <p> Infectious mononucleosis (IM), commonly known as <em>kissing disease,</em> is a viral syndrome resulting
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