US Pharm. 2017;42(5):HS-7-HS-10.
Infectious mononucleosis (IM or Mono) is usually caused by the Epstein–Barr virus (EBV), which is a member of the herpes virus family. This virus was discovered by the renowned Russian pediatrician Nil Filatov in 1885. IM is characterized by a triad of symptoms: fever, tonsillar pharyngitis, and lymphadenopathy. It is primarily spread through saliva, and those who are infected can spread the disease weeks before symptoms develop. Spreading may occur through objects such as drinking glasses or toothbrushes and can be prevented by not sharing personal items or kissing infected individuals. Drinking enough fluids, getting sufficient rest, and taking pain medications such as acetaminophen and ibuprofen are the best recommendations. There is no vaccine for EBV, and mono generally gets better on its own.1
Mono is primarily diagnosed based on the symptoms and can be confirmed with blood tests for specific antibodies. Another typical finding is increased blood lymphocytes, of which more than 10% are atypical. Mono most commonly affects those between the ages of 15 to 24 years in the developed world. In the developing world, people are more often infected in early childhood when the symptoms are less severe. In those between ages 16 and 20 years, it is the cause of about 8% of sore throats. Mononucleosis was first described in the 1920s and is generally known as the kissing disease. The relationship between EBV and IM was established when a laboratory worker was infected with EBV and developed IM. A few other viruses may also cause the disease.2
The background, pathogenesis, clinical manifestation, diagnosis, and treatment of IM in adults and adolescents will be briefly reviewed in this article.
Epstein-Barr virus is spread by contact between sensitive people and EBV carriers. The virus has not been recovered from environmental sources, suggesting that humans are the major reservoir.
In the United States, antibodies to EBV have been demonstrated in all population groups with 25% to 50% in lower socioeconomic groups. Many attribute this finding to personal contact and poor personal hygiene among children, which provides opportunities for early acquisition and further spreading of EBV. The peak incidence of infection is in the 15- to 24-year age range.3 IM is relatively uncommon in adults (less than 2% of pharyngitis cases). The vast majority of adults are not affected by this infection because of prior exposure.4
The incidence of clinical infection is approximately 30 times higher in whites than in blacks in the U.S.5 In addition, IM occurs more frequently in same-sex twins and first-degree siblings, compared with second- and third-degree relatives. Thus, genetic factors may influence who develops clinical disease.6
Following IM, the virus may be shed in salivary secretions at high levels for as long as 6 months after onset of illness. Although it should be pointed out that once infected with EBV, the virus might be intermittently found in the oropharynx for decades.7 The virus can persistently shed in the oropharynx of patients with IM for up to 18 months following clinical recovery. Intrafamilial spread among siblings has also been reported.8
In addition, EBV has been isolated in breast milk from healthy nursing mothers. However, in one study there was no difference in EBV seropositive status between exclusively nursed or bottle-fed infants, suggesting that breastfeeding is not an important route of transmission.9 EBV has also been isolated in male seminal fluid, suggesting that transmission may occur sexually. Sexual activity before college admission was very much associated with an increased risk of EBV-seropositive status; however, despite the recovery of EBV in genital secretions, studies have been unable to determine whether EBV was acquired through an oral or genital route.10
Exposure to EBV in the back and sidewalls of the throat allows replication of the virus, release of EBV into the oropharyngeal secretions, and infection of B cells in the lymphoid-rich areas of the oropharynx. EBV-infected B cells are responsible for the dissemination of infection throughout the lymphoreticular system. The incubation period prior to the development of symptoms averages 4 to 8 weeks.11
EBV becomes a lifelong infection as it establishes latency with periodic reactivation. On the other hand, insufficient cellular immune responses may result in a poorly controlled EBV infection and/or generate an EBV-induced malignancy. Even with sufficient immune responses, some epidemiological studies have linked IM to increased risks of other conditions, such as Hodgkin’s lymphoma.12
Some studies have linked acquisition of infection to increased risks for autoimmune disorders, such as multiple sclerosis or systemic lupus erythematosus. Such associations require additional research to prove causation as well as to determine whether they could be a result of direct viral or immunological consequences. Such concerns have heightened interest in exploring potential preventative strategies, such as an EBV vaccine.13
Regular features of IM include fever, pharyngitis, adenopathy, fatigue, and atypical lymphocytosis.1 The syndrome is often followed by malaise, headache, and low-grade fever before development of the more specific symptoms.
Although fever and sore throat may be resolved in a month, fatigue may be persistent and severe. Fatigue appears to be more common in and have a more profound impact on exercise abilities in young female university students compared with male students.14
Lymph-node involvement in IM is typically symmetrical and more commonly involves the posterior cervical rather than the anterior chains. Lymphadenopathy may also become more generalized, which distinguishes IM from other causes of pharyngitis. Lymphadenopathy peaks in the first week and then gradually subsides over 2 to 3 weeks. A history of sore throat is often accompanied by pharyngeal inflammation and tonsillar oozing, which may appear white, gray-green, or even necrotic.15
Many patients with acute EBV infection have relatively mild disease, and some present with pharyngitis and tonsillitis in the absence of a full-blown IM syndrome.16
Many patients present with fever and lymphadenopathy without pharyngitis, the so-called typhoidal form of illness. Very young or older adults frequently do not develop the classic clinical syndrome. Fever is common among older individuals and can last for several weeks.17
A maculopapular rash almost always occurs following the administration of ampicillin or amoxicillin and several other antibiotics. The incidence of rash associated with beta-lactams was initially reported to be as high as 70% to 90%, but it is probably lower. The mechanism responsible for the rash is not well understood.18 Development of a drug-related rash during IM does not appear to presage a true drug allergy, as patients subsequently tolerate ampicillin without an adverse reaction.
Neurologic manifestations such as Guillain-Barré syndrome, facial and other cranial nerve palsies, meningoencephalitis, aseptic meningitis, peripheral neuritis, optic neuritis, and encephalomyelitis occur 2 to 4 weeks or more after initial symptom onset.19
Epstein-Barr virus–induced IM should be suspected when an adolescent or young adult complains of sore throat, fever, and fatigue and also has lymphadenopathy and pharyngitis on physical examination.1 The presence of palatal petechiae, splenomegaly, and posterior cervical adenopathy are highly suggestive of IM, while the absence of enlarged posterior cervical lymph nodes and fatigue make the diagnosis less likely.20
Supportive evidence of EBV infection is derived from the observation of lymphocytosis and increased circulating atypical lymphocytes along with a positive heterophile antibody test (a rapid test for antibodies produced against EBV). Patients with fever, lymphadenopathy, and pharyngitis should also have a diagnostic evaluation for streptococcal infection by culture or antigen testing. Reactive heterophile antibodies in a patient with a compatible syndrome are diagnostic of EBV infection and, therefore, are the diagnostic tests of choice in most clinical settings in North America.1 The heterophile test does not have the same specificity and sensitivity in young children.
Other rapid diagnostic tests use enzyme-linked immunosorbent assay (ELISA) techniques. The sensitivity and specificity of the rapid kits approach 85% to 100%.21
Patients with suspected IM based upon history and physical examination should have a white blood cell count with differential and a heterophile test. If the heterophile test is positive, no further testing is necessary if the clinical scenario is compatible with typical IM. If the heterophile test is negative but there is still a strong clinical suspicion of EBV infection, the monospot test can be repeated since testing can be negative early in clinical illness.22
The first laboratory finding in association with IM is lymphocytosis, defined as an absolute count >4500/microliter or, on peripheral smear, a differential count >50%. The smear may also identify significant atypical lymphocytosis, defined as >10% of total lymphocytes. The total white blood cell count in patients with IM averages 12,000 to 18,000/microliter, although it may be much higher.23
Unusual hematologic manifestations include hemolytic anemia, thrombocytopenia, aplastic anemia, thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome, and disseminated intravascular coagulation. Some of these complications result from EBV-induced production of antibodies directed against red blood cells, white blood cells, and platelets.23
Elevated aminotransferases are seen in the vast majority of patients, but are self-limited. Abnormal liver function tests in a patient with pharyngitis strongly suggest the diagnostic possibility of IM.24
Patients with fever, pharyngitis, and lymphadenopathy may have streptococcal, cytomegalovirus, acute HIV, or, rarely, toxoplasma infection.25
Streptococcal infection is not usually accompanied by significant fatigue or splenomegaly on examination. Pharyngitis associated with cytomegalovirus (CMV) tends to be extremely mild, if present at all, but may cause liver-function test elevations, as does acute EBV. Differentiating between IM caused by EBV and a similar syndrome due to CMV or HIV infection is often not possible clinically. Diagnostic testing is particularly important if the patient is pregnant, since CMV, HIV, and toxoplasma infections can have significant adverse effects on pregnancy outcomes.26
Supportive care is the primary requirement for EBV infection and individuals with IM. Acetaminophen or nonsteroidal anti-inflammatory drugs are recommended for the treatment of fever, throat discomfort, and malaise. Consumption of adequate fluids and nutrition is also important, as is adequate rest, although complete bed rest is unnecessary.27
The use of corticosteroids in the treatment of EBV-induced IM has been controversial. Many do not recommend corticosteroid therapy for routine cases of IM since it is generally a self-limited illness, and there are theoretical concerns about immunosuppression during clinical illness with a virus that has been causally linked to a variety of malignancies. However, corticosteroids may be considered in the management of patients with some EBV-associated complications.27
Corticosteroids, as well as consultation with an airway specialist, are warranted in individuals with difficulty breathing or dyspnea in the recumbent position. Data on dosing and duration of corticosteroid therapy in patients with IM is very limited. Once clinical improvement has been achieved, tapering the corticosteroid dose slowly (e.g., over 7 to 14 days) is recommended.28
Corticosteroid therapy may also be considered in those with severe life-threatening infection (e.g., major liver failure) or other complications such as severe hemolytic or aplastic anemia. Data supporting benefits from corticosteroids in these settings are less vigorous than the data found for the treatment of IM-related airway obstruction.28
Acyclovir is an antiviral drug that inhibits permissive EBV infection through inhibition of EBV DNA polymerase, but has no effect on latent infection or power to cure the infection. Specific therapy of acute EBV infections with intravenous and oral formulations of acyclovir has been studied, but a significant clinical benefit has not been shown.29 However, there are recent reports that valcyclovir reduces the frequency of EBV-infected B-cells when given over a long period.30
As IM mostly affects teenagers and young adults, many of whom participate in competitive sports and other forms of exercise, an obvious question is when to recommend restarting athletic activities. More than 50% of patients with IM develop splenic enlargement within the first 2 weeks of symptoms; as a result, the main issue is avoiding activities that may precipitate splenic rupture.31
For athletes planning to resume noncontact sports, training can be gradually restarted 3 weeks from symptom onset. This recommendation assumes that participants avoid any activities capable of causing chest or abdominal trauma.31
For more vigorous contact sports (including football, gymnastics, rugby, hockey, lacrosse, wrestling, diving, and basketball) or activities associated with increased intra-abdominal pressure (such as weightlifting) that may carry a higher risk of splenic injury, athletes should wait a minimum of 4 weeks after illness onset.32
To resume training, clinicians wait for resolution of objective symptoms as well as an improvement in the athlete’s sense of well being. For the first few days, athletes should train at reduced levels compared to their premorbid state, increasing activities gradually, as tolerated. Competitive athletes may not attain pre-illness strength for 3 or more months. The physician should be especially careful when giving recommendations to athletes who may unduly pressure themselves or be pressured by others to resume vigorous activity too soon.33
IM is an acute illness due to EBV infection, which occurs mainly in adolescents and young adults. IM is classically characterized by fever, pharyngitis, fatigue, and lymphadenopathy. Other findings can include splenomegaly and palatal petechiae. Cervical lymphadenopathy tends to involve the posterior chain of lymph nodes.
Rare complications include splenic rupture and airway obstruction. A generalized maculopapular, urticarial, or petechial rash—more common following the administration of ampicillin or amoxicillin—is seen occasionally. Common laboratory findings include an absolute or relative lymphocytosis, an increased proportion of atypical lymphocytes, and elevated aminotransferases.
Patients with suspected IM, based upon the history and physical examination, should have a white blood cell count with differential and heterophile tests. In addition, patients should also have a diagnostic evaluation for streptococcal infection by culture or antigen testing. Currently, there is no vaccine against EBV. While no antiviral therapy is effective, recent studies have shed light on the efforts to control EBV using valcyclovir over a long period of time.
1. Evans AS. The history of infectious mononucleosis. Am J Med Sci. 1974;267:189-195.
2. Henle G, Henle W, Diehl V. Relation of Burkitt’s tumor-associated herpes-type virus to infectious mononucleosis. Proc Natl Acad Sci. 1968;59:94-101.
3. Heath CW Jr, Brodsky AL, Potolsky AI. Infectious mononucleosis in a general population. Am J Epidemiol. 1972;95:46-52.
4. Aronson MD, Komaroff AL, Pass TM, et al. Heterophil antibody in adults with sore throat: frequency and clinical presentation. Ann Intern Med. 1982;96:505-508.
5. Nye FJ. Social class and infectious mononucleosis. J Hyg. 1973;71:145-149.
6. Rostgaard K, Wohlfahrt J, Hjalgrim H. A genetic basis for infectious mononucleosis: evidence from a family study of hospitalized cases in Denmark. Clin Infect Dis. 2014;58:1684-1689.
7. Balfour HH Jr, Holman CJ, Hokanson KM, et al. A prospective clinical study of Epstein-Barr virus and host interactions during acute infectious mononucleosis. J Infect Dis. 2005;192:1505-1512.
8. Fleisher GR, Pasquariello PS, Warren WS, et al. Intrafamilial transmission of Epstein-Barr virus infections. J Pediatr. 1981;98:16-19.
9. Kusuhara K, Takabayashi A, Ueda K, et al. Breast milk is not a significant source for early Epstein-Barr virus or human herpesvirus 6 infection in infants: a seroepidemiologic study in 2 endemic areas of human T-cell lymphotropic virus type I in Japan. Microbiol Immunol. 1997;41:309-312.
10. Israele V, Shirley P, Sixbey JW. Excretion of the Epstein-Barr virus from the genital tract of men. J Infect Dis. 1991;163:1341-1343.
11. Anagnostopoulos I, Hummel M, Kreschel C, et al. Immunophenotype, and distribution of latently and/or productively Epstein-Barr virus-infected cells in acute infectious mononucleosis: implications for the interindividual infection route of Epstein-Barr virus. Blood. 1995;85:744.
12. Hjalgrim H, Smedby KE, Rostgaard K, et al. Infectious mononucleosis, childhood social environment, and risk of Hodgkin lymphoma. Cancer Res. 2007;67:2382-2388.
13. Sokal EM, Hoppenbrouwers K, Vandermeulen C, et al. Recombinant gp350 vaccine for infectious mononucleosis: a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein-Barr virus vaccine in healthy young adults. J Infect Dis. 2007;196:1749-1753.
14. 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. Clin Infect Dis. 2010;50:699-706.
15. Aronson MD, Komaroff AL, Pass TM, et al. Heterophil antibody in adults with sore throat: frequency and clinical presentation. Ann Intern Med 1982;96:505-508.
16. Yoda K, Sata T, Kurata T, Aramaki H. Oropharyngotonsillitis associated with nonprimary Epstein-Barr virus infection. Arch Otolaryngol Head Neck Surg. 2000;126:185-193.
17. Auwaerter PG. Infectious mononucleosis in middle age. JAMA. 1999;281:454-459.
18. Horwitz CA, Henle W, Henle G, et al. Heterophil-negative infectious mononucleosis and mononucleosis-like illnesses. Laboratory confirmation of 43 cases. Am J Med. 1977;63:947-957.
19. Tselis A, Duman R, Storch GA, et al. Epstein-Barr virus encephalomyelitis diagnosed by polymerase chain reaction: detection of the genome in the CSF. Neurology 1997;48:1351-1355.
20. Ebell MH, Call M, Shinholser J, et. Al. Does this patient have infectious mononucleosis?: the rational clinical examination systematic review. JAMA 2016;315:1502-1509.
21. Linderholm M, Boman J, Juto P, et al. Comparative evaluation of nine kits for rapid diagnosis of infectious mononucleosis and Epstein-Barr virus-specific serology. J Clin Microbiol. 1994;32:259-261.
22. Basson V, Sharp AA. Monospot: a differential slide test for infectious mononucleosis. J Clin Pathol. 1969;22:324-325.
23. Auwaerter PG. Infectious mononucleosis in middle age. JAMA. 1999;281:454-459.
24. Ghosh A, Ghoshal UC, Kochhar R, et al. Infectious mononucleosis hepatitis: report of two patients. Indian J Gastroenterol. 1997;16:113-114.
25. Klemola E, Von Essen R, Henle G, et al. Infectious-mononucleosis-like disease with negative heterophil agglutination test. Clinical features in relation to Epstein-Barr virus and cytomegalovirus antibodies. J Infect Dis. 1970;121:608-614.
26. Gaines H, von Sydow M, Pehrson PO, et al. Clinical picture of primary HIV infection presenting as a glandular-fever-like illness. BMJ. 1988;297:1363-1368.
27. Rezk E, Nofal YH, Hamzeh A, et al. Steroids for symptom control in infectious mononucleosis. Cochrane Database Syst Rev. 2015(11):CD004402.
28. Thompson SK, Doerr TD, Hengerer AS. Infectious mononucleosis and corticosteroids: management practices and outcomes. Arch Otolaryngol Head Neck Surg. 2005;131:900-904.
29. Tynell E, Aurelius E, Brandell A, et al. Acyclovir and prednisolone treatment of acute infectious mononucleosis: a multicenter, double-blind, placebo-controlled study. J Infect Dis. 1996;174:324-331.
30. Hoshino Y, Katano H, Zou P. et al. Long-term administration of valcyclovir. J Virology, 2009;83(22):11857-11861.
31. Burroughs KE. Athletes resuming activity after infectious mononucleosis. Arch Fam Med. 2000;9:1122-1123.
32. Ali J. Spontaneous rupture of the spleen in patients with infectious mononucleosis. Can J Surg. 1993;36:49-52.
33. Waninger KN, Harcke HT. Determination of safe return to play for athletes recovering from infectious mononucleosis: a review of the literature. Clin J Sport Med 2005; 15:41-416.
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