MICROBIOLOGY

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

CLINICAL

  • Subclinical infection typical (90%), especially in children.
    • Infection is more prevalent and occurs at earlier age in lower socioeconomic groups.
    • EBV mostly spread by asymptomatic salivary shedding.
    • In the developed world, 95% eventually infected by age 40, estimated 30-40% college freshman are uninfected.
  • Primary symptomatic infection = infectious mononucleosis (IM)
    • IM peaks in teens and early 20s, with 30-77% adolescents/adults experiencing symptoms with primary infection.
  • Ddx mononucleosis syndrome: includes Group A Streptococcal pharyngitis, acute CMV, acute HIV, toxoplasmosis, influenza, viral hepatitis, rubella, drug reactions.
  • Laboratory hallmarks of primary infection, clinically symptomatic:
    • Elevated WBC (10-18K) typical with lymphocytosis (40->60%) common.
    • Atypical lymphocytes [ Fig] usually comprise 10-30+% of circulating lymphocytes.
  • Dx: predominant method is by detection of either non-specific heterophile antibodies or specific EBV serology.
    • Heterophile antibody (+) 90% [Monospot™], negatives may turn (+) on repeat 5-10d later.
      • Assay predominantly used in US; advantages 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 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 EBV as cause of mono-like syndrome.
        • Occasional low levels may be seen earlier in authentic acute infection.
    • EBV PCR: most helpful for diagnosis of EBV-driven lymphoma, especially for CNS lymphoma in HIV (+) pts.
      • Sensitivity reported as high as 97%, specificity 98% but may be less.
      • Also useful with EBV-related meningoencephalitis.
  • Do not check EBV titers merely as 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%), 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 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, 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 spontaneous, typically 1-2 wks post initial sx), encephalitis (typically >1mo after onset of sx).
    • Severity of IM appears to correlate with intensity of EBV viral load as well as CD8+ cytotoxic T cell response.
  • Other processes related to EBV (not necessarily primary infection):
    • HEENT: oral hairy leukoplakia (HIV), nasopharyngeal carcinoma
    • HEME: cause of Burkitt’s lymphoma, implicated in other lymphomas, especially HIV-related, post-transplant lymphoproliferative disorder.
      • Hemophagocytic lymphohistiocytosis (HLH): may be primary or secondary cause due to EBV.
        • Features include fever, pancytopenia, hepatosplenomegaly, elevated triglycerides and low fibrinogen levels.
        • Spectrum includes mild/self-limiting to aggressive/fatal.
        • The chemotherapeutic agent etopside considered a primary treatment consideration, also possibly rituximab, anti-thymocyte globulin (ATG) or stem cell transplantation.
  • EBV not an acknowledged cause of Chronic Fatigue Syndrome, but fatigue is common following infectious mononucleosis.
  • Chronic active EBV (rare): pancytopenia, chronic LN, pneumonitis, abnl LFTs > 8wks. Prove by repeated positive EBV blood PCR studies and consistent clinical picture. This is not "chronic EBV" that is sometimes used as a term for Chronic Fatigue Syndrome.

TREATMENT

Infectious Mononucleosis

  • IM usually self-limited < 3wks average, rest and supportive care. Little high quality evidence to back recommendations.
  • Athletes with IM: no training, sports x 3 wks from onset; if contact sport e.g., football, no sports x 4 wks from onset and no splenomegaly (document by imaging such as ultrasound if wish to participate < 4 wks).
    • Counsel patients to avoid traumatic activities, and seek evaluation for any significant abdominal pain, LUQ pain or L shoulder pain (referred from spleen, Kehr’s sign) that might represent splenic injury.
    • Splenic rupture: may require emergent splenectomy; some may be closely observed to retain spleen. Transfuse as necessary.
  • Corticosteroids (prednisone 40-60mg/d) indicated for airway obstruction, severe thrombocytopenia or hemolytic anemia.
    • Some give for severe pharyngitis or constitutional sx (controversial).
  • Acyclovir, valacylovir, ganciclovir: antivirals have no role in IM. Reduces oral viral shedding, but no clinical benefit.

Selected Drug Comments

Drug

Recommendation

Acyclovir

No proven worth in IM other than reduction in oral shedding.

Ganciclovir

Though more active than acyclovir for EBV, no proven worth in IM other than reduction in oral shedding. Some use to treat CNS EBV acute infections but controversial.

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 suggestive that IM is associated with subsequent increased risk of Hodgkin’s lymphoma or multiple sclerosis [18] [12].
  • By age 40, an estimated 95% of adults are infected.
  • Spleen size may be normally increased in some taller individuals, so splenomegaly "persisting" beyond four weeks may be normal variant (3-7%) [15].

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 tip-off toward IM rather than GAS pharyngitis.
  • Roommates, household contacts: no increased risk IM routinely.
  • EBV-specific ABs 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 can cause post-infectious fatigue after IM in ~10%). DON’T draw serologies for chronic fatigue sx.--no data to support as cause.

Basis for recommendation

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

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

  2. Tynell E et al: Acyclovir and prednisolone treatment of acute infectious mononucleosis: a multicenter, double-blind, placebo-controlled study. J Infect Dis 174:324, 1996  [PMID:8699062]

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

References

  1. Ali AS et al: Epstein- Barr Virus: Clinical and Epidemiological Revisits and Genetic Basis of Oncogenesis. Open Virol J 9:7, 2015  [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), gastric carcinomas.

  2. Auwaerter PG: Infectious mononucleosis in middle age. JAMA 281:454, 1999  [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-age to elderly patients all of whom had definitive evidence of a current EBV primary infection. Protracted fever, jaundice, pleural effusion, anemia, or the Guillain-Barre syndrome were dominant clinical findings among these patients. Clinically, older patients appear to have less pharyngitis, LN, splenomegaly while fever & hepatitis is more prominent.

  3. Katon W et al: Infectious mononucleosis: psychological symptoms during acute and subacute phases of illness. Gen Hosp Psychiatry 21:21, 1999 Jan-Feb  [PMID:10068917]

    Comment: Although anecdotal reports suggest that anxiety and depressive disorders maybe precipitated by IM, 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 criteria for DSM-III-R psychiatric illness. Problems that regarding anxiety, depression or fatigue that persisted beyond two or six months was best correlated with lower psychosocial premorbid functioning rather than any severity index regarding acute IM.

  4. Balfour HH et al: Behavioral, virologic, and immunologic factors associated with acquisition and severity of primary Epstein-Barr virus infection in university students. J Infect Dis 207:80, 2013  [PMID:23100562]

    Comment: Prospective study starting with US college freshmen/women demonstrated that IM is still the "kissing disease." In this study, 546 students 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. Severity of illness correlated positively with both blood EBV load (P = .015) and CD8(+) lymphocytosis (P = .0003).
    Study take home points 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, severity of infection is likely a consequence a vigorous, mainly cytotoxic T cell immune response.
    Rating: Important

  5. Bozlak S et al: Cervical lymphadenopathies in children: A prospective clinical cohort study. Int J Pediatr Otorhinolaryngol 82:81, 2016  [PMID:26857321]

    Comment: Infections was 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 thought to be responsible for 27%.

  6. Morris MC, Edmunds WJ: The changing epidemiology of infectious mononucleosis? J Infect 45:107, 2002  [PMID:12217713]

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

  7. Taga K, Taga H, Tosato G: Diagnosis of atypical cases of infectious mononucleosis. Clin Infect Dis 33:83, 2001  [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, then it is incumbent upon the physician suspicious of IM to ask for a manual differential that may then visualize circulating atypical lymphocytes.

  8. Auwaerter PG: Recent advances in the understanding of infectious mononucleosis: are prospects improved for treatment or control? Expert Rev Anti Infect Ther 4:1039, 2006  [PMID:17181419]

    Comment: Describes some newer potential antiviral agents and vaccines, but nothing truly on the horizon for effective therapy known.

  9. Dunmire SK et al: The Incubation Period of Primary Epstein-Barr Virus Infection: Viral Dynamics and Immunologic Events. PLoS Pathog 11:, 2015  [PMID:26624012]

    Comment: On average, patients come to clinical attention about six weeks after acquisition of primary EBV. These authors had a prospective longitudinal cohort and were able to 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 therefore is a result of the loss of viral replicative control backed up by finding only high levels of virus just about the same time or at the time of clincial presentation. Very low levels of EBV in blood were detected ~ 3 wks prior. There was no expansion of cytotoxic T cells (CD8) in this early perior and only upon onset of high level virus and clinical disease.

  10. Horwitz CA 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 72:807, 1979  [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.

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

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

  12. Handel AE et al: An updated meta-analysis of risk of multiple sclerosis following infectious mononucleosis. PLoS One [PMID:20824132]

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

  13. Hosey RG et al: Ultrasound assessment of spleen size in collegiate athletes. Br J Sports Med 40:251, 2006  [PMID:16505083]

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

  14. Höcker B et al: Epidemiology and morbidity of Epstein-Barr virus infection in pediatric renal transplant recipients: a multicenter, prospective study. Clin Infect Dis 56:84, 2013  [PMID:23042966]

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

  15. Montoya JG 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 85:2101, 2013  [PMID:23959519]

    Comment: Small study suggesting benefit in patients with elevated titers to EBV and HHV-6. IFteb sycg small studies (n=30) don’t hold up in larger studies when considering this likely heterogenous disorder.

  16. Odumade OA, Hogquist KA, Balfour HH: Progress and problems in understanding and managing primary Epstein-Barr virus infections. Clin Microbiol Rev 24:193, 2011  [PMID:21233512]

    Comment: Comprehensive review regarding pathogenesis, diagnosis and other strategies related to initial infection with EBV. Although some small studies have shown effect on viral shedding with valacyclovir, there are no recommendations for anti-viral therapy. Recent vaccine trials are also reviewed.

  17. Steeper TA et al: Heterophil-negative mononucleosis-like illnesses with atypical lymphocytosis in patients undergoing seroconversions to the human immunodeficiency virus. Am J Clin Pathol 90:169, 1988  [PMID:3394657]

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

  18. Higgins CD et al: A study of risk factors for acquisition of Epstein-Barr virus and its subtypes. J Infect Dis 195:474, 2007  [PMID:17230406]

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

  19. Cinque P et al: Epstein-Barr virus DNA in cerebrospinal fluid from patients with AIDS-related primary lymphoma of the central nervous system. Lancet 342:398, 1993  [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.

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

    Comment: Due to the lack of good data (RCTs), authors could not find enough evidence to back the use of corticosteroids. In 8/10 studies, most found no benefit. Two appeared to find less pharyngitis at 12 hours (eight-day course odds ratio (OR) 21.00, 95% confidence interval (CI) 1.94 to 227.20; one-dose OR 4.20, 95% CI 1.08 to 16.32), but the benefit was not maintained. When combined with an antiviral, steroids yielded less pain in throat between days two to four (OR 0.31, 95% CI 0.09 to 1.08) compared to placebo. For the two trials set out to measure safety; they documented no major adverse effects.

  21. 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 38:1629, 2004  [PMID:15156453]

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

  22. Schuler JG, Filtzer H: Spontaneous splenic rupture. The role of nonoperative management. Arch Surg 130:662, 1995  [PMID:7763176]

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

  23. Linderholm M et al: Comparative evaluation of nine kits for rapid diagnosis of infectious mononucleosis and Epstein-Barr virus-specific serology. J Clin Microbiol 32:259, 1994  [PMID:8126196]

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

  24. Hjalgrim H et al: Characteristics of Hodgkin's lymphoma after infectious mononucleosis. N Engl J Med 349:1324, 2003  [PMID:14523140]

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

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

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

  26. Torre D, Tambini R: Acyclovir for treatment of infectious mononucleosis: a meta-analysis. Scand J Infect Dis 31:543, 1999  [PMID:10680982]

    Comment: This meta-analysis examined 5 randomized controlled trials (RCT), involving 339 patients with acute infectious mononucleosis (IM) treated with acyclovir (ACV) was performed. There was a trend towards clinical effectiveness of ACV treatment, but no statistically significant results were achieved. In contrast, a significant reduction in the rate of oropharyngeal EBV shedding was observed at the end of the therapy. However, no difference in EBV shedding was observed 3 weeks later. There was no significant difference on adverse events in the groups of patients treated with ACV or placebo.
    Rating: Important

  27. Sokal EM 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 196:1749, 2007  [PMID:18190254]

    Comment: This phase II vaccine study sought to determine whether acute EBV infection or IM could be prevented through the immunization of 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, and at 1 month and 5 months, with follow-up for a total of 18 months. The authors found that immunization 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 end point of preventing IM showed an efficacy of 78% (95% CI, 1- 96%), but did not halt asymptomatic acquisition of EBV. Adverse side effects were no different 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 to be safe and it generated 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, 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 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 well be worthwhile in industrialized countries where there is some evidence suggesting that IM is increasing in incidence as well as severity. Given the immunological complexity of EBV infection, the question of whether a vaccine strategy can be safely employed will not be quickly answered, as longterm studies will likely be needed.

  28. Maki DG, Reich RM: Infectious mononucleosis in the athlete. Diagnosis, complications, and management. Am J Sports Med 10:162, 1982 May-Jun  [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, and it rarely occurs beyond the third week from onset of clinical symptoms.

Media

Atypical Lymphocytes

A. Normal LymphocyteB. Enlarged, atypical lymphocyte with more cytoplasma and bilobed nucleousC. So-called "Dutch Skirting" caused by red blood cells indenting lymphocyte outer membraneSource: Paul G. Auwaerter, MD

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Last updated: May 29, 2016