MICROBIOLOGY

• Epstein-Barr virus, a gamma herpes virus also known as human herpesvirus (HHV-4).
• Establishes life-long latent infection.

CLINICAL

• Subclinical infection is typical (90%), especially in children.
  
  • Infection is more prevalent and occurs earlier in lower socioeconomic groups.
  • EBV is mostly spread by asymptomatic salivary shedding.
  • In high-income countries, 95% are eventually infected by age 40, though an estimated 30-40% of college freshmen are uninfected.
• Primary symptomatic infection = infectious mononucleosis (IM)
  
  • IM peaks in teens and early 20s, with 30-77% of adolescents/adults experiencing symptoms with primary infection.
• Ddx mononucleosis syndrome: includes Group A Streptococcal pharyngitis, acute CMV, acute HIV, toxoplasmosis, influenza, viral hepatitis, rubella, and drug reactions.
• Laboratory hallmarks of primary infection, clinically symptomatic:
  
  • Elevated WBC (10-18K) with lymphocytosis (40->60%) common.
    • Atypical lymphocytes [Fig] usually comprise 10-30+% of circulating lymphocytes.
  • Elevated LFTs, jaundice may occur at any age but increases with older ages.
• Dx: The predominant methods are by detecting non-specific heterophile antibodies or specific EBV serology.
  
  • Heterophile antibody (+) 90% [Monospot™], negatives may turn (+) on repeat 5-10d later.
    • The assay is predominantly used in the U.S.; its advantages are inexpensive and rapid.
    • Approximately 10% of primary EBV infection/IM remain heterophile-negative.
    • False (+) heterophile rare: lymphoma, hepatitis, SLE, HIV.
  • If still suspect IM, order EBV-specific serology:
    
    • EBV capsid IgM and IgG (+) with negative EBNA diagnostic of acute infection if performed < 4-6 wks from the onset of symptoms.
    • This test may be ordered instead of Monospot, often the test of choice in many European countries.
    • Positive EBNA in patients suspected of IM (< 4-6wks sx) argues that capsid IgM/IgG titers indicate remote infection therefore NOT supportive of acute EBV as the cause of the mono-like syndrome.
      • Occasional low levels may be seen earlier in authentic acute infection.
  • EBV PCR: most helpful for diagnosing EBV-driven lymphoma, especially for CNS lymphoma in HIV (+) pts.
    • Sensitivity was reported as high as 97%, specificity 98% but maybe less.
    • Also helpful with EBV-related meningoencephalitis.
• Do not check EBV titers merely as an evaluation of fatigue. EBV is not an explanation, as currently understood, for chronic fatigue syndrome.

SITES OF INFECTION

• Classic triad infectious mononucleosis: fever, pharyngitis, lymphadenopathy (especially posterior cervical).
  • Common:
    
    • Elevated LFTs (ALT usually < 300)
    • Splenomegaly (50%)
    • Hepatomegaly
    • Rash (10%)
      • Variable appearing rash that is erythematous and blotchy is often found on the torso.
      • Rash following amoxicillin administration occurs >98-100% with IM.
  • Uncommon: hemolytic anemia, cytopenias, pneumonitis, carditis, seizures, palsies, Guillain-Barré, encephalitis (late).
    • Abdominal pain: if present in a patient with proven or suspected IM, should be considered to have a splenic rupture until proven otherwise.
  • Pts. > 35yrs. with IM have atypical presentations with less pharyngitis and lymphadenopathy.
    • These older patients instead present with more of a primary hepatitis picture, FUO or uncommon complications.
  • Life-threatening IM complications: tonsillar airway obstruction (early), splenic rupture (may be spontaneous, typically 1-2 wks post initial sx), encephalitis (typically >1mo after the onset of sx).
  • The severity of IM appears to correlate with the intensity of EBV viral load and CD8⁺ cytotoxic T-cell response.
• Other processes related to EBV (not necessarily primary infection):
  
  • HEENT:
    • Oral hairy leukoplakia (HIV)
    • Nasopharyngeal carcinoma
  • HEME: a cause of Burkitt’s lymphoma, implicated in other lymphomas, especially HIV-related, post-transplant lymphoproliferative disorder.
  • EBV is not an acknowledged cause of chronic fatigue syndrome, but fatigue is common following infectious mononucleosis.
  • Chronic active EBV (CAEBV, rare): pancytopenia, chronic LN, pneumonitis, abnormal LFTs > 8wks. Prove by repeated positive high plasma or whole blood EBV blood PCR studies and consistent clinical picture.
    • This is not "chronic EBV," which is sometimes used as a term for Chronic Fatigue Syndrome.
    • An infiltrative disorder that requires hematopoietic stem cell transplantation (HSCT) for a cure.
  • Hemophagocytic lymphohistiocytosis (HLH):
    • EBV is among the causes of non-genetic acquired HLH, a hyperinflammatory syndrome. The frequency appears to be more common in Asian populations.
      
      • Early recognition and treatment are essential otherwise, high mortality.
      • Suspect in a severely ill patient with infectious mononucleosis that doesn’t improve after 3-4 weeks with ongoing fever, progressive cytopenias and LFT abnormalities.
    • HLH should be considered if fever, cytopenias, elevated LFTs, hepatosplenomegaly, or coagulopathy exist and may develop usually subacutely without IM initial diagnosis.
    • Diagnosis based on clinical criteria, one set of measures proposed by Henter 2007, needing at least 5 of 8 (see: Table Clinical Criteria).
    • Treatment: dexamethasone and etoposide are temporizing, and HSCT is often required for a cure.

• Post-treatment lymphoproliferative disorder (PTLD):
  • A complication of both solid organ transplantation (SOT) and allogeneic HSCT.
  • It is one of the most common posttransplant malignancies, some driven by EBV, but others are of unknown cause.
    • Risk greatest early after transplantation, usually when immunosuppressive regimens are most intense.
    • EBV-negative PTLD tends to occur later, months to years after transplantation.
    • The risk for developing PTLD ally painless lymphadenopathy.
  • Four classification types:
    • Early lesions: often respond to a reduction in immunosuppression.
    • Polymorphic PTLD: a mixture of lymphoid cell types.
    • Monomorphic PTLD: due to one cell type, the most common form of PTLD usually causes non-Hodgkin B-cell lymphoma, but other types may occur. Of the B-types, diffuse large B-cell lymphoma is most common though Burkitt’s is seen and more rarely other types.
    • Classical Hodgkin’s lymphoma: rare
  • Treatment: depending on the type and underlying issues, usually decided upon working with a transplant physician and oncologist. Standard options range from immunosuppressive drug reduction, rituximab, chemotherapy or radiotherapy.

TREATMENT

FOLLOW UP

• Fatigue may persist after IM in 10-20% > 1 month.
  • Customary advice is to increase activities as tolerated. Enforced bed-rest is counterproductive.
• Some information is suggestive that IM is associated with a subsequent increased risk of Hodgkin’s lymphoma or multiple sclerosis[23][18].
• By age 40, an estimated 95% of adults are infected.
• Spleen size may be generally increased in some taller individuals, so splenomegaly "persisting" beyond four weeks may be a normal variant (3-7%)[21].

OTHER INFORMATION

• By definition, infectious mononucleosis is only caused by primary EBV infection. Other infectious causes should be described as causing a mononucleosis-like syndrome.
• Pharyngitis and abnormal LFTs are tip-offs toward IM rather than GAS pharyngitis.
• Roommates, household contacts: no increased risk IM routinely.
• EBV-specific antibody profile is helpful, especially if heterophile (-) IM.
  
  • EBV capsid IgM & IgG (+) with EBNA (-) = IM-if sx < 4-6wks.
  • Acute EBV excluded if (+) EBNA since EBNA only expressed >6wks acute infection as latency established.
• EBV is not a cause of Chronic Fatigue Syndrome (although it can cause post-infectious fatigue after IM in ~10%). Don’t draw serologies for chronic fatigue sx.--no data to support as a cause.

Basis for recommendation

1. Lennon P, Crotty M, Fenton JE. Infectious mononucleosis. BMJ. 2015;350:h1825.  [PMID:25899165]

   Comment: Direction to frequent clinical diagnostic and therapeutic problems and return to sports that face practitioners. Most is expert opinion based on thin data such as retrospective or observational studies rather than RCTs.
   

2. 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(2):324-31.  [PMID:8699062]

   Comment: The combination of corticosteroid and acyclovir offered no clinical benefit in IM.
   

References

3. de Cassan S, Thompson MJ, Perera R, et al. Corticosteroids as standalone or add-on treatment for sore throat. Cochrane Database Syst Rev. 2020;5:CD008268.  [PMID:32356360]

   Comment: Meta-analysis of eight trials with more adults than children found a modest benefit. The issue is that with IM, there is some evidence that the use of steroids may heighten risk for outcomes such as lymphoma and autoimmune disease when population databases are analyzed.
   

4. Andrei G, Trompet E, Snoeck R. Novel Therapeutics for Epstein⁻Barr Virus. Molecules. 2019;24(5).  [PMID:30871092]

   Comment: As existing antivirals have little effect on EBV, there is much interest in new approaches, especially for PTLDS, HLH-related disease and CAEBV.
   

5. Risma KA, Marsh RA. Hemophagocytic Lymphohistiocytosis: Clinical Presentations and Diagnosis. J Allergy Clin Immunol Pract. 2019;7(3):824-832.  [PMID:30557712]

   Comment: General overview of HLH, including genetic and sporadic.
   

6. Bollard CM, Cohen JI. How I treat T-cell chronic active Epstein-Barr virus disease. Blood. 2018;131(26):2899-2905.  [PMID:29712633]

   Comment: Dr. Cohen has the most experience with CAEBV in the U.S. HSCT is the only true curative option suggesting that early diagnosis is important to allow sufficient health for good outcomes.
   

7. Kimura H, Cohen JI. Chronic Active Epstein-Barr Virus Disease. Front Immunol. 2017;8:1867.  [PMID:29375552]

   Comment: Mechanisms are not entirely understood, but in CAEBV, host responses don’t control the virus resulting in markedly elevated levels of EBV DNA in the blood and infiltration of organs by EBV-positive lymphocytes. Patients often present with fever, lymphadenopathy, splenomegaly, EBV hepatitis, or pancytopenia. Over time, these patients develop progressive immunodeficiency and if not treated, succumb to opportunistic infections, hemophagocytosis, multiorgan failure, or EBV-positive lymphomas. Patients with CAEBV in the United States most often present with a disease involving B or T cells, while in Asia, the disease usually involves T or NK cells. The only proven effective treatment for the disease is hematopoietic stem cell transplantation.
   

8. Marsh RA. Epstein-Barr Virus and Hemophagocytic Lymphohistiocytosis. Front Immunol. 2017;8:1902.  [PMID:29358936]

   Comment: HLH should be considered patients with IM who don’t improve after four weeks with continued fever, perhaps progressive jaundice, LFT abnormalities and severe cytopenias.
   

9. Bozlak S, Varkal MA, Yildiz I, et al. Cervical lymphadenopathies in children: A prospective clinical cohort study. Int J Pediatr Otorhinolaryngol. 2016;82:81-7.  [PMID:26857321]

   Comment: Infections were the leading category in the 41.3% of patients with diagnosed entities (of 218 total) in this study from Turkey. Of the 27% (n = 59) with infections, EBV was considered responsible for 27%.
   

10. De Paor M, O'Brien K, Fahey T, et al. Antiviral agents for infectious mononucleosis (glandular fever). Cochrane Database Syst Rev. 2016;12:CD011487.  [PMID:27933614]

    Comment: Seven RCTs were examined that judge the effectiveness of antivirals (acyclovir, valganciclovir and valacyclovir) in IM. Authors judge the quality of evidence as very low. The majority of included studies were at unclear or high risk of bias, so questions remain about the effectiveness of this intervention. Although two of the 12 outcomes have results that favor treatment over control, the quality of the evidence of these results is very low and may not be clinically meaningful.
    

11. Rezk E, Nofal YH, Hamzeh A, et al. Steroids for symptom control in infectious mononucleosis. Cochrane Database Syst Rev. 2015.  [PMID:26558642]

    Comment: This 2015 update of earlier 2012 did not find any new data compared to the earlier Cochrane review that examined seven trials with 362 participants. Available data was low quality with nothing to support their use; however, this is due to the paucity of trials.
    

12. Dunmire SK, Grimm JM, Schmeling DO, et al. The Incubation Period of Primary Epstein-Barr Virus Infection: Viral Dynamics and Immunologic Events. PLoS Pathog. 2015;11(12):e1005286.  [PMID:26624012]

    Comment: On average, patients come to clinical attention about six weeks after acquiring primary EBV. These authors had a prospective longitudinal cohort and could follow events in the pre-patent period. They found little virus in oral secretions until 1 week before symptom onset. Authors postulate that clinical EBV results from the loss of viral replicative control backed up by finding only high levels of the virus just about the same time or at the time of clinical presentation. Very low levels of EBV in blood were detected ~ 3 wks prior. There was no cytotoxic T cells (CD8) expansion in this early period and only upon the onset of high-level virus and clinical disease.
    

13. Ali AS, Al-Shraim M, Al-Hakami AM, et al. Epstein- Barr Virus: Clinical and Epidemiological Revisits and Genetic Basis of Oncogenesis. Open Virol J. 2015;9:7-28.  [PMID:26862355]

    Comment: Review of malignancies with certain and associated EBV, including Burkitt’s lymphoma, Hodgkin’s disease, post-transplant lymphoproliferative disorders (PTLD) and T-cell lymphomas (e.g., peripheral T-cell lymphomas; PTCL and Anaplastic large cell lymphomas; ALCL). It is also linked to epithelial tumors such as nasopharyngeal carcinoma (NPC), and gastric carcinomas.
    

14. Balfour HH, Odumade OA, Schmeling DO, et al. Behavioral, virologic, and immunologic factors associated with acquisition and severity of primary Epstein-Barr virus infection in university students. J Infect Dis. 2013;207(1):80-8.  [PMID:23100562]

    Comment: A prospective study starting with US college freshmen/women demonstrated that IM is still the "kissing disease." In this study, 546 students were screened, 202 (37%) were antibody negative, and 143 antibody-negative students were enrolled. During a median of 3 years of observation, 66 subjects experienced primary infection. Of these, 77% had infectious mononucleosis, 12% had atypical symptoms, and 11% were asymptomatic. Subjects reporting deep kissing with or without coitus had the same higher risk of infection than those reporting no kissing (P < .01). Viremia was transient, but median oral shedding was 175 days. The severity of illness correlated positively with both blood EBV load (P = .015) and CD8(+) lymphocytosis (P = .0003).
    The study take-home point for this author is that this is one of the first "modern" studies in years. Over one-third of US students in this Midwest university were EBV seronegative. Also, the majority were symptomatic with infection. Although some have suggested EBV is an STD, this was not supported in this study. As others have found, the severity of infection is likely a consequence of a vigorous, mainly cytotoxic T-cell immune response.
    Rating: Important
    

15. Höcker B, Fickenscher H, Delecluse HJ, et al. Epidemiology and morbidity of Epstein-Barr virus infection in pediatric renal transplant recipients: a multicenter, prospective study. Clin Infect Dis. 2013;56(1):84-92.  [PMID:23042966]

    Comment: A small prospective study of primary EBV infection in children with renal transplants found no correlation with the intensity or duration of EBV viral load for post-transplant lymphoproliferative disorder. The study was too small to determine if other factors were at play.
    

16. Green M, Michaels MG. Epstein-Barr virus infection and posttransplant lymphoproliferative disorder. Am J Transplant. 2013;13 Suppl 3:41-54; quiz 54.  [PMID:23347213]

    Comment: A helpful and thorough review of PTLD management, which is beyond the scope of this module. Traditionally, lowering immunosuppression is the key strategy, although other therapies, including rituximab (anti-CD20 monoclonal antibody) and traditional chemotherapy, are sometimes used.
    

17. Montoya JG, Kogelnik AM, Bhangoo M, et al. Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome. J Med Virol. 2013;85(12):2101-9.  [PMID:23959519]

    Comment: A small study suggested benefits in patients with elevated titers to EBV and HHV-6. Small studies (n=30) don’t hold up usually in larger studies when considering this likely heterogeneous disorder.
    

18. Handel AE, Williamson AJ, Disanto G, et al. An updated meta-analysis of risk of multiple sclerosis following infectious mononucleosis. PLoS One. 2010;5(9).  [PMID:20824132]

    Comment:
    Authors expand upon a prior meta-analysis but incorporate newer, larger studies. They found a risk (RR) 2.17 for MS following IM.
    

19. Higgins CD, Swerdlow AJ, Macsween KF, et al. A study of risk factors for acquisition of Epstein-Barr virus and its subtypes. J Infect Dis. 2007;195(4):474-82.  [PMID:17230406]

    Comment: One of several studies perhaps suggests the role of sexual transmission for EBV. What is difficult is to divorce potential oral from genital exposures.
    

20. 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(12):1749-53.  [PMID:18190254]

    Comment: This phase II vaccine study sought to determine whether acute EBV infection or IM could be prevented by immunizing naive young adults. This was a randomized, double-blind trial using a recombinant gp350 vaccine that prompts antibody development against a key viral antigen that facilitates EBV entry into B lymphocytes. Immunizations were carried out at initiation, 1 month and 5 months, with follow-up for a total of 18 months. The authors found that vaccination with the gp350 vaccine yielded detectable antibody response in 98.7% of subjects (95% CI, 85.5-97.9%). By the end of the 18-month study period, the primary endpoint of preventing IM showed an efficacy of 78% (95% CI, 1- 96%) but did not halt the asymptomatic acquisition of EBV. Adverse side effects were no differences between the vaccine and placebo groups. The group receiving the gp350 vaccine had no cases of IM once the three series of immunizations were completed, compared to the placebo group that continued to develop IM. This trial suggests that in the intent-to-treat analysis, the gp350 vaccine was protective against the development of IM — although the small study design guaranteed wide confidence intervals. Immunization appeared safe, generating reliable seroconversion, suggesting that the vaccine is a candidate for study in larger populations. Whether such a vaccine can interrupt the malignancy potential of EBV depends on whether the significant immune dysregulation as a consequence of IM is a leading driver. If, instead, the oncogenic potential is related to viral infection alone, then this vaccine is unlikely to yield this specific benefit since it does not appear to halt the acquisition of the EBV virus. Regardless, since there is no reliable medical therapy for IM that shortens illness or postinfectious fatigue duration, a vaccine strategy could be worthwhile in industrialized countries where there is some evidence suggesting that IM is increasing in incidence and severity. Given the immunological complexity of EBV infection, whether a vaccine strategy can be safely employed will not be quickly answered, as long-term studies will likely be needed.
    

21. Hosey RG, Mattacola CG, Kriss V, et al. Ultrasound assessment of spleen size in collegiate athletes. Br J Sports Med. 2006;40(3):251-4; discussion 251-4.  [PMID:16505083]

    Comment: Taller/larger people may have spleens bigger than customary ultrasound measurements. This doesn’t mean they must refrain from activities beyond 4-6 weeks after IM.
    

22. Ivers LC, Kim AY, Sax PE. Predictive value of polymerase chain reaction of cerebrospinal fluid for detection of Epstein-Barr virus to establish the diagnosis of HIV-related primary central nervous system lymphoma. Clin Infect Dis. 2004;38(11):1629-32.  [PMID:15156453]

    Comment: Small series refuting the claimed high sensitivity/specificity of EBV CSF PCR. Here 26 patients were studied with CNS processes but PCR only had 29% positive predictive value, and a specificity 79%. This study more likely reflects real-life statistics in evaluating a diffuse set of CNS conditions in HIV. Authors suggest tests useful for ruling out lymphoma but not diagnosing it without a brain biopsy.
    Rating: Important
    

23. Hjalgrim H, Askling J, Rostgaard K, et al. Characteristics of Hodgkin's lymphoma after infectious mononucleosis. N Engl J Med. 2003;349(14):1324-32.  [PMID:14523140]

    Comment: The study suggests an approximately 40x increased risk of HL after IM during four year study period.
    Rating: Important
    

24. Morris MC, Edmunds WJ. The changing epidemiology of infectious mononucleosis? J Infect. 2002;45(2):107-9.  [PMID:12217713]

    Comment: British series suggests that the infection is causing increased hospitalization rates of adolescents and adults compared to surveys of IM in the 1970s and 1980s. The authors suggest that there has been a dramatic decline in childhood infections of low severity, while infection acquired later in life is more likely to yield severe symptoms.
    

25. Taga K, Taga H, Tosato G. Diagnosis of atypical cases of infectious mononucleosis. Clin Infect Dis. 2001;33(1):83-8.  [PMID:11389499]

    Comment: Cases of primary EBV with unusual features are particularly challenging diagnostically, especially when automated hematologic analyzers do not flag leukocyte counts to be inspected manually for the presence of atypical lymphocytes. When WBC #’s are within normal range, it is incumbent upon the physician suspicious of IM to ask for a manual differential that may visualize circulating atypical lymphocytes.
    

26. Auwaerter PG. Infectious mononucleosis in middle age. JAMA. 1999;281(5):454-9.  [PMID:9952206]

    Comment: Although Epstein-Barr-virus (EBV)-induced infectious mononucleosis usually occurs in young adults between the ages of 15 and 30, if it occurs in older individuals, it frequently presents diagnostic problems. These two reports described middle-aged to elderly patients with definitive evidence of a current EBV primary infection. Protracted fever, jaundice, pleural effusion, anemia, or Guillain-Barre syndrome were dominant clinical findings among these patients. Clinically, older patients appear to have less pharyngitis, LN, and splenomegaly, while fever & hepatitis is more prominent.
    

27. Rickinson AB, Moss DJ. Human cytotoxic T lymphocyte responses to Epstein-Barr virus infection. Annu Rev Immunol. 1997;15:405-31.  [PMID:9143694]

    Comment: The circulating atypical lymphocytes of IM have long been known to be not EBV-infected B lymphocytes but instead highly activated cytotoxic T lymphocytes (CTL) important for clearly lytic phase primary infection. Investigators have sought to control the problematic problem of EBV-related lymphoproliferative disorders by using CTL infusion in bone marrow transplant candidates, which may hold some success by immunomodulation of this challenging problem.
    

28. Schuler JG, Filtzer H. Spontaneous splenic rupture. The role of nonoperative management. Arch Surg. 1995;130(6):662-5.  [PMID:7763176]

    Comment: Splenic rupture in IM has traditionally been handled by splenectomy. However, recognizing the long-term risks of overwhelming sepsis due to the post-splenectomy state, this case series and literature review advocate conservative management only if hemodynamics are stable and the blood transfusion requirement does not exceed two units of blood.
    

29. 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(1):259-61.  [PMID:8126196]

    Comment: The study compared nine commonly used kits and EBV-specific serology for infectious mononucleosis. The sensitivities and specificities of the rapid kits (Monospot and similar) varied from 63 to 84% and 84 to 100%, respectively.
    

30. Cinque P, Brytting M, Vago L, et al. Epstein-Barr virus DNA in cerebrospinal fluid from patients with AIDS-related primary lymphoma of the central nervous system. Lancet. 1993;342(8868):398-401.  [PMID:8101902]

    Comment: Retrospective analysis of autopsy-proven cases of AIDS-related CNS lymphoma documenting that PCR for EBV DNA in CSF was 100% sensitive and 98.5% specific. For these patients, the EBV CSF PCR may be useful as a diagnostic tumor marker obviating the need for brain biopsy in a patient with compatible neuroimaging.
    

31. Steeper TA, Horwitz CA, Hanson M, et al. Heterophil-negative mononucleosis-like illnesses with atypical lymphocytosis in patients undergoing seroconversions to the human immunodeficiency virus. Am J Clin Pathol. 1988;90(2):169-74.  [PMID:3394657]

    Comment: One of a number of reports highlighting that acute HIV seroconversion must be entertained as a diagnosis of heterophile-negative mononucleosis-like illnesses.
    

32. Horwitz CA, Henle W, Henle G, et al. Persistent falsely positive rapid tests for infectious mononucleosis. Report of five cases with four--six-year follow-up data. Am J Clin Pathol. 1979;72(5):807-11.  [PMID:228546]

    Comment: Five patients followed for >4yrs with persistently positive rapid heterophile (Monospot) tests without evidence of illness, thereby emphasizing that false positives unassociated with any illnesses may occur.
    

33. Katon W, Russo J, Ashley RL, et al. Infectious mononucleosis: psychological symptoms during acute and subacute phases of illness. Gen Hosp Psychiatry. 1999;21(1):21-9.  [PMID:10068917]

    Comment: Although anecdotal reports suggest that IM may precipitate anxiety and depressive disorders, this has not been examined rigorously. This study in high school and college students found that although transient psychological distress was common during acute infection, few patients met the criteria for DSM-III-R psychiatric illness. Problems regarding anxiety, depression or fatigue that persisted beyond two or six months were best correlated with lower psychosocial premorbid functioning rather than any severity index regarding acute IM.
    

34. Maki DG, Reich RM. Infectious mononucleosis in the athlete. Diagnosis, complications, and management. Am J Sports Med. 1982;10(3):162-73.  [PMID:7114352]

    Comment: Though dated from an imaging perspective, this study examines some of the thorny issues regarding restriction from athletic training and participation. The most fearsome complication is splenic rupture, which rarely occurs beyond the third week of the onset of clinical symptoms.
    

Media

Atypical Lymphocytes

A. Normal Lymphocyte

B. Enlarged, atypical lymphocyte with more cytoplasma and bilobed nucleous

C. So-called "Dutch Skirting" caused by red blood cells indenting lymphocyte outer membrane

Source: Paul G. Auwaerter, MD