Epstein Barr Virus Infections

• Introduction.
• Primary infection.
  • Infectious mononucleosis.
• Latency.
• Reactivation.
• Complications associated with EBV infection.
  • Lymphoma.
  • Nasopharyngeal carcinoma.
  • Hairy leukoplakia.

Introduction

• EBV (HHV4) is a gamma-herpesvirus that only naturally occurs in humans. There are no animal reservoirs.
• EBV was named after Tony Epstein and Yvonne Barr who were the two scientists who first isolated and described the virus in 1964 from lymphoma samples collected by Denis Burkitt.
• EBV is of direct relevance to the practice of dentistry as:
  • Appropriate Cross Infection practices will prevent unnecessary spread of EBV infections in the dental surgery.
  • It causes several different diseases of importance including:
    • Infectious Mononucleosis which:
      • Is common.
      • Has oral manifestations.
      • Needs to be distinguished from other causes of Glandular Fever-Like Syndromes.
    • Lymphomas and Nasopharyngeal Carcinoma which are associated with high morbidity and mortality.
    • Hairy Leukoplakia which means that HIV Infection has to be considered.
• Because of this diversity of pathologies, and the different causes of essential that dentists understand the importance of EBV as a common human pathogen, or important diagnoses will be missed.
• A fundamental property of EBV is that it is able to induce cellular proliferation. This is rarely neoplastic, although EBV was the first virus to be implicated in the pathogenesis of human cancers.
• There are obvious advantages to vaccination against EBV infection, but to date, it has not been possible to produce an effective vaccine.
• EBV, in common with other HHVs, causes primary infection, latency for life (in B-lymphocytes), and reactivation that may be symptomatic.

1. Primary Infection

• Secretions from an infected person shedding virus are transferred directly (not by aerosol) to mucosal surfaces of an uninfected individual. EBV can also be spread via blood transfusions and organ transplantation.
  • In developed countries, infection prevalence is 50% in 5 year old children and increases to 95% of young adults.
  • Infection occurs earlier in life in developing countries.
• EBV infects different human cell types including epithelial cells and lymphocytes.
• Primary infection with EBV can be:
  • Asymptomatic - most, particularly in developing countries where infection occurs early in life.
  • Symptomatic- when it causes Infectious Mononucleosis (also known as glandular fever).
• Whether primary infection is symptomatic or asymptomatic is determined by several factors including:
  • Age: Primary infection in children is usually subclinical, whereas in adolescents or young adults, it is more likley to be symptomatic:
    • IM has been described as the 'kissing disease'. This reflects a common mechanism of spread in adolescents or young adults.
    • The greater chance of symptomatic infection in adolescents and young adults may partially reflect a larger innoculum of EBV being passed to the uninfected individual.
  • Immune status: Symptomatic primary infection is more likely in immunocompromised than immunocompetent patients.

   

Clinical Features of Infectious Mononucleosis

• There is an incubation period of 30-50 days.
• During the acute phase of primary EBV infection, symptoms typically include:
  • Sore throat that may be associated with dysphagia.
  • Marked fatigue with associated functional impairment.
• Clinical signs commonly include:
  • Pharyngitis and tonsillitis (with extension to involve the soft palate in some) - the involved mucosa is:
    • Erythematous with erosions and small petechiae.
    • Odematous.
    • Coated with a greyish exudate.
  • Cervical lymphadenopathy - tender or painful lymph nodes:
    • Including involvement of the posterior cervical lymph nodes in 60%.
      • These lymph nodes are involved in few other conditions.

Palatal petechiae, erosions and a greyish exudate in a patient with infectious mononucleosis.

• Other clinical signs may occur including:
  • Fever (probably not as common as once thought).
  • Splenomegaly.
  • Cough.
  • Arthralgia.
  • Nausea.
• In most patients there is resolution of the acute signs and symptoms within a month.
  • However, lethargy can persist for several weeks (or even months) longer.

Investigation and Subsequent Management

• IM may be suspected from the clinical history and examination, but the diagnosis must be confirmed by special investigations due to the overlap in clinical features that occur in Glandular Fever-Like Syndromes.
• EBV replication occurs in B-lymphocytes resulting in inappropriate proliferation and death. The Full Blood Count (FBC) is transiently grossly abnormal and is characterised in the acute phase by:
  • An absolute lymphocytosis (i.e. an increased number of circulating lymphocytes).
  • The presence of many atypical lymphocytes (virally-infected B-lymphocytes induce an unusually strong T-lymphocyte response).
• EBV infection induces production of antibodies.
  • The Monospot Test is used as a screening test in suspected IM and was developed from the Paul-Bunnell Test.
    • It detects heterophil antibodies, which although present in 85% of patients with IM, are not raised against EBV antigens.
    • The Monospot Test is widely used as a first line investigation due to problems associated with specific EBV antibody assay interpretation.
    • However, if the Monospot Test is negative, and EBV infection is suspected, anti-EBV antibodies should be investigated.
  • Detection of specific anti-EBV IgM antibodies (e.g. IgM anti-VCA antibodies) confirms acute infection, but due to the long incubation period of IM, the transient IgM response has often resolved prior to testing.
  • The presence of anti-EBV IgG antibodies confirms EBV infection. Recent infection is suggested by a 4-fold rise in antibody titre over a 4-week period. If serum samples are available from prior to the illness, then it may be possible to demonstrate seroconversion.
• Liver involvement can cause transient hepatitis with derrangement of Liver Function Tests (LFTs).

• Once the diagnosis has been established, management is supportive in the majority of patients.
  • Primary symptoms and abnormalities of the FBC and LFTs have typcially resolved within one month.
  • However, some patients experience lethargy for several weeks or months. This can be severe and debilitating.
• Do not prescribe either Amphotericin or Amoxycillin in a patient with infectious mononucleosis. This will cause a rash.
  • Although the rash has a dramatic appearance, it is not associated with longterm adverse sequelae.
• In otherwise well patients, the transient hepatitis is of little clinical significance.
  • However, in a patient with pre-existing liver disease, impaired hepartic function will be compromised further.
    • For example, particular care must be taken with either blood-letting procedures or prescription of drugs metabolised by the liver.

2. Latency

• Latency is established at the time of primary infection.
• During this time the host defences are unable to detect and eliminate EBV from the body.
  • Accordingly, EBV infections are lifelong.
  • This is important in the development of the long-term complications of EBV infection which are discussed below.

3. Reactivation

• EBV can be reactivated from the latent state.
• Control of reactivation remains poorly understood, although immune status is important.
• In immunocompetent individuals reactivation is common and mostly asymptomatic, but infective EBV is shed in secretions such as saliva.
  • In one study, infectious EBV was detected at some point over a 15 month period in the saliva of 90% of healthy, asymptomatic adults.
    • A quarter of the study group were shedding EBV on every occasion that they were tested.
• Reactivation of latent EBV causes symptomatic disease of variable severity in a small number of patients (probably less than 10%).
• Features of symptomatic EBV reactivation include fatigue and general malaise.
  • There is a spectrum of severity.
  • In some, attacks can be severely debilitating and impact on the individuals ability to lead the working and home life that they were prior to their illness. There may be associated depression.
• Symptomatic reactivation may be recurrent in some patients.

Complications Associated With EBV Infection

• Infectious Mononucleosis is the commonest clinical manifestation of EBV infection, either as a primary infection or due to symptomatic reactivation from latency.
• However, EBV contributes to the pathogenesis of several other human diseases including:
  • Lymphomas.
  • Nasopharyngeal carcinoma.
  • Hairy Leukoplakia.

   

Lymphomas

• EBV causes inappropriate lymphocyte proliferation, but only a small proportion of EBV-associated lymphocyte proliferation results in malignancy.
• EBV latency is associated with different types of lymphoma including:
  • Non-Hodgkin's Lymphoma - a common type of lymphoma in the U.K. that may present in different ways:
    • Systemic symptoms (common):
      • Firm, rubbery, non-tender lymphadenopathy (especially in the neck and axillae).
      • Constitutional symptoms such as night sweats, weight loss. loss of energy, fever or pruritis.
    • Oral lesions (uncommon):
      • Firm, elastic, reddish/purple swellings that may be ulcerated.
        • Fauces, palate or gingivae are commonly involved.
      • Intraosseous lesions that cause:
        • Pain, altered sensation, bony swelling, loosening of teeth or pathological fractures.
  • Burkitt's Lymphoma - a common childhood lymphoma in Africa.
    • Intraosseous mandibular lesions are common and are associated with symptoms as described above.
• Patients who have compromised cellular immunity, for example those with AIDS, are particulary prone to developing EBV-associated lymphomas.

Nasopharyngeal Carcinoma

• In South-East Asia it is the third most common cancer.
  • In European populations it is a rare cancer.
  • However, because of modern population movements, consideration should always be given to the geographical and racial origins of all patients.
• Tumour growth is often aymptomatic and presentation, typically with cervical lymphadenopathy, is late. The prognosis is then poor.
• Screening programmes to detect anti-EBV antibodies have been successfully used to detect early nasopharyngeal carcinomas that are amenable to successful treatment.

Hairy Leukoplakia

• EBV-induced epithelial hyperplasia causes corregated white lesions that have been termed Hairy Leukoplakia (HL).
  • HL mostly involves the lateral border of the tongue, but can involve other oral sites including the buccal mucosae.
  • The clinical appearance is usually distinctive enough to make a diagnosis. Where doubt exists, an incisional biopsy should be undertaken.
  • Aside from the appearance, HL is asymptomatic, and many patients with HL are unaware of the lesions.
• The presence of HL means that HIV infection must be excluded.
  • HL can occur in the absence of HIV infection, for example in organ transplant patients who are immunosuppressed.
• No specific management is required.
  • HL is not a premalignant condition.
  • HL can resolve as a consequence of successful management of the underlying condition.
    • For example, in patients with HIV infection, HL typically resolves in response to HAART.

Hairy leukoplakia involving the lateral border of the tongue in a patient with AIDS.

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