Infectious mononucleosis - EBV

PATHOGENESIS

• Epstein-Barr virus is a herpesvirus that primarily infects the epithelial cells of the oropharynx and tonsils.

• Infection in the tonsillar crypt epithelial cells results in viral replication and shedding.

• Transmission of EBV requires intimate contact with the saliva of an infected person, as happens with kissing or sharing a drinking glass.

• Viral shedding is highest in the first year postinfection and can continue throughout life in smaller amounts, thereby extending the length of transmissibility.

• EBV infects B lymphocytes, resulting in the proliferation and secretion of a number of different types of antibodies, including EBV-specific antibodies; heterophile antibodies; and autoantibodies, such as rheumatoid factor and antinuclear antibodies. The secretion of these various antibodies is referred to as polyclonal activity. After the virus has invaded the host, it is kept in check by the action of natural killer cells and cytotoxic T cells. This cellular immune response limits the extent of primary IM and controls chronic infection.

• The symptoms of acute IM are a direct result of cyto­kines that are released from activated T cells. Because the symptoms of EBV infection are T-cell mediated, the initial viral load will determine the level of T-cell response and, thus, the severity of illness. Increased viral load will lead to increased T-cell response and increased symptoms. EBV can remain latent in infected B lymphocytes, which serve as lifelong viral reservoirs, expressing only a restricted number of EBV genes that are hidden from host immune surveillance cells. If the virus is reactivated, shedding can occur in the saliva and genital secretions of asymptomatic persons.

EPIDEMIOLOGY AND RISK FACTORS

• Most EBV transmission occurs through direct contact with saliva, but transmission also occurs during the birth process and through exposure to blood products.

• The virus has been identified in both male and female genital tracts, leading to a possible risk of infection after sexual contact with an infected partner.

• The overall incidence of IM in the United States is 500 cases per 10,000 persons per year.

• Symptomatic IM tends to occur in adolescents and young adults, although it can affect patients of any age.

• IM is found equally in all groups; there are no predispositions based on gender, race, ethnicity, or sexual orientation.

• Older adults are usually not susceptible because 95% have had prior exposure to EBV and possess lifetime latent infection.

• Infection control techniques have lowered the risk of infection.

• No specific seasonal pattern has been identified.

CLINICAL PRESENTATION

• Primary IM has an incubation period of 30 to 50 days postexposure and is a self-limiting disease.

• Most cases are found in young adults between 14 and 24 years of age.

• Older adults often present with clinical manifestations of hepatitis.

• Young children present with nonspecific mild symptoms that can conceal the diagnosis.

• The clinical diagnosis is suggested by classic symptoms of fatigue, malaise, fever, adenopathy, and pharyngitis.

• Prodromal symptoms include malaise, headache, and low-grade fever.

• Symptoms of EBV can range from a mild flulike illness to a prolonged, debilitating disease.

• Typical physical examination findings include posterior cervical, axillary, and/or inguinal lymphadenopathy.

• Ten percent of patients present with a generalized maculopapular, urticarial, or petechial rash.

• These clinical findings should alert the clinician to suspect EBV infection.

• An enlarged spleen is found in 15% to 65% percent of IM patients.

• If abdominal discomfort and/or decreased hematocrit is noted, splenic rupture, though rare, can occur in 0.5% to 1% of cases.

• EBV can affect virtually any organ system and can be associated with such complications as hepatitis, pneumonia, myocarditis, mesenteric adenitis, myositis, genital ulcers, and renal failure.

• The symptoms of IM typically last 2 to 4 weeks, although fatigue and myalgias can persist for months.

• The diagnosis of IM is usually eliminated by the absence of fatigue and lymphadenopathy. Given that the initial presentation of the acute retroviral syndrome of HIV is clinically indistinguishable from IM (sore throat; lymphadenopathy, often including splenomegaly; fever; and malaise), a sexual/drug history should be obtained if the patient is at risk for HIV infection.

DIFFERENTIAL DIAGNOSIS

• When patients present with fever, rash, weakness, myalgia, and headache, acute retroviral syndrome is always a consideration. Prompt diagnosis is crucial because early treatment can reduce the risk of complications and transmission.

• Approximately 90% of cases of mononucleosis like syndrome are due to EBV.

• Another 5% to 10% of patients are actually exhibiting a mononucleosis like syndrome caused by other infectious agents, such as cytomegalovirus (CMV).

• Infection with CMV is more common in older populations.

• Complaints of pharyngitis raise the possibility of streptococcal or CMV infection.

• Bacterial infections, such as acute streptococcal pharyngitis, do not manifest with the atypical lymphocytes commonly seen in EBV. The pharyngitis, lymphadenopathy, and splenomegaly associated with CMV are usually mild. A patient exhibiting signs of splenomegaly and lymphadenopathy should have additional testing to rule out lymphoma. Protozoal etiologies of mononucleosis syndrome manifest with mild symptoms in the immunocompetent patient. A mononucleosis like syndrome with atypical lymphocytosis can be induced by such drugs as phenytoin (Dilantin, Phenytek, generics), carbamazepine, isoniazid, or minocycline.

LABORATORY TESTING

Any patient presenting with the classic symptoms of IM should have a CBC and undergo screening for EBV (rapid test for heterophile antibodies), group A streptococcal pharyngitis (rapid antigen testing, throat culture), and quantitative polymerase chain reaction (PCR) test for possible HIV exposure. Hematologic findings provide clues in the analysis of IM, while serologic tests confirm infection. Characteristic laboratory findings of IM include an absolute lymphocytosis of greater than 50% with 10% atypical lymphocytes (activated cytotoxic T cells).

The heterophile antibody, or monospot, test is a rapid latex agglutination serologic screening test for IgM antibodies to Paul-Bunnell antigens found on the surface of EBV-infected B cells. Heterophile antibodies are produced during the acute phase of IM. Test results are positive in up to 40% of patients during the first week of illness and in 90% of patients in later weeks. Because the heterophile antibody is present in many patients during the acute phase of illness, it is considered a good screening test for patients showing symptoms of the disease. Patients who have symptoms of IM but are negative for the heterophile antibody should have further serum testing for EBV-specific antibodies via indirect immunofluorescence assay (IFA). The two tests together, the heterophile antibody and EBV-specific antibody tests, have a sensitivity of 95% to 99%. The IFA has a high specificity and is therefore considered the gold standard for diagnosis. False-positive heterophile antibody test results can occur in patients with lymphoma, viral hepatitis, malaria, and autoimmune disease.

Some examples of EBV-specific antibodies include antibodies to early antigen (EA) and to viral capsid antigen (VCA). These antibodies are detected by IFA on EBV-infected cells. Antibody to EA is noted in the serum during the initial stage of viral replication and is usually not detectable 3 to 6 months after acute infection. IgM antibody against the viral capsid antigens (VCA-IgM) is the most useful marker for identification of acute IM because it appears at the onset of symptoms and usually disappears by 3 months. The presence of EA and VCA-IgM confirms primary infection with EBV. Absence of VCA-IgM is strong evidence against primary EBV infection. VCA-IgG antibodies are detectable at the onset of IM and remain positive for life. Their presence indicates development of immunity and is not useful in distinguishing primary from past infection. IgG antibodies to Epstein-Barr nuclear antigen (EBNA) become evident 6 to 8 weeks after onset of symptoms and remain positive for life. Since this marker appears later in the disease process, it offers strong evidence against primary EBV infection. Clinician must be able to differentiate between active contagious infection, pathologic infection, and chronic latent infection.

While negative heterophile antibody results might help to rule out IM, the clinician should always remain vigilant for the presence of mononucleosis like illnesses, such as acute retroviral syndrome, toxoplasmosis, or CMV or human herpesvirus-6 as the etiology of infection. If the patient is pregnant, follow up with nucleic acid testing for CMV and HIV because these infections have been linked to pregnancy and fetal complications. When suspicion for EBV is high despite failure to detect antibody, testing for EBV DNA on B cells is warranted.⁷ Also keep in mind that testing too early in the course of illness can result in decreased sensitivity because the immune response is too low.

CDC guideline for lab diagnosis

VCA-IgG antibodies are detectable at the onset of IM and remain positive for life. People are considered to have a primary EBV infection if they have anti-VCA IgM but do not have antibody to EBNA. Other results that strongly suggest a primary infection are a high or rising level of anti-VCA IgG and no antibody to EBNA after at least four weeks of illness. He does not portray that serology.

MANAGEMENT

The mainstay treatment for primary IM is supportive care. Encourage adequate fluid and nutritional intake. Analgesics and antipyretics, such as acetaminophen or NSAIDs, relieve symptoms of fever, throat discomfort, and myalgia. Corticosteroids, once thought to be safe, should be reserved for patients with severe complications. Routine use can lead to serious side effects, including immunosuppression and bacterial superinfection.¹¹Immunosuppression during a viral illness has been linked to malignancy. Prednisone 40 to 60 mg/day over 2 to 3 days with tapering over 2 weeks can prevent airway obstruction if there is severe tonsillar hypertrophy; autoimmune hemolytic anemia; severe thrombocytopenia; or progressive neurologic disease, such as multiple sclerosis (MS).^2,6 Patients should refrain from participation in any sport for a minimum of 3 weeks after the onset of illness and from participation in strenuous contact sports for 4 weeks after the onset of illness to avoid the risk of splenic rupture.⁶Restrictions should be placed on intimate contact because viral shedding is greatest during acute IM. The clinician can prevent transmission by observing universal precautions, including proper hand washing. Infected patients should avoid donating blood products, which carries a small risk of transmission.

The likelihood of a cutaneous reaction to penicillin and other antibiotics is increased in patients with acute IM. A maculopapular rash can occur in up to 95% of patients treated with antimicrobials.^6,13 The pathophysiology remains unclear, although EBV might alter the immune status of the host, enhancing a hypersensitivity reaction to certain drugs and their metabolites.¹³ Most studies have found that this immune response reverses on resolution of symptoms, but one study found persistence of a delayed immune reaction to penicillin in a small number of some patients.¹⁴ All patients presenting with rash and a history of recent acute IM should undergo allergy testing.

COMPLICATIONS

Most cases of mononucleosis resolve without sequelae in 3 to 4 weeks. Potentially life-threatening complications include splenic rupture, upper airway obstruction secondary to lymphoid hyperplasia, and mucosal edema.

Ineffective immune T-cell response to EBV infection can result in excessive B-cell proliferation and in B-lymphocyte malignancies and lymphomas. The presence of EBV DNA in the malignant cells of neoplasms suggests that EBV might contribute to the pathogenesis of such malignancies as Hodgkin disease, Burkitt lymphoma, nasopharyngeal carcinoma, and gastric tumors.^5,7,15 EBV is capable of infecting B lymphocytes, squamous epithelial cells, glandular epithelial cells, smooth muscle cells, T cells, natural killer cells, and follicular dendritic cells. If an infected cell transforms into a malignant cell, every daughter cell will be similar.⁷Eventually, EBV might be utilized as a tumor marker in malignancy, assisting in staging, prognosis, and response to therapy.⁷ There is a rare increased risk of hematologic, neurologic, and autoimmune disease. Elevated antibody levels against EBV have been found in those affected with systemic lupus erythematosus (SLE), MS, and rheumatoid arthritis (RA), among others.¹⁶

Male patients with X-linked lymphoproliferative syndrome appear normal until a primary IM infection turns fatal as a result of lack of T cell response. Because these patients are unable to limit infection of B lymphocytes, death occurs due to bone marrow failure, irreversible hepatitis, and malignant lymphoma.⁶ Hypogammaglobulinemia, B lymphocyte lymphoma, or both develop in those who do survive.^6,12 Hemophagocytic lymphohistiocytosis manifests as prolonged fever, lymphadenopathy, hepatosplenomegaly, rash, hepatic dysfunction, and cytopenia.^6,12 The most common complications of mononucleosis syndrome are presented in Table 3.

ONGOING RESEARCH

Antiviral agents, specifically valacyclovir (Valtrex, generics), show some promise in the management of IM. A small randomized, controlled clinical trial, conducted by the FDA, enrolled 20 Minnesota college students with laboratory-confirmed primary EBV. The oral washings of subjects who took valacyclovir showed a transient decrease in Epstein-Barr viral load (leading to a decrease in severity of symptoms and sequelae).¹⁷ A lower viral load also translates to a reduction in viral shedding and subsequent decreased transmission. Discontinuation of valacyclovir was associated with a rebound in oral viral load. Because this study was small, results need to be confirmed with a larger placebo-controlled trial. Nucleoside analogues, such as famciclovir (Famvir, generics) or valganciclovir (Valcyte), might be attractive candidates for prospective trials.

Research is ongoing to establish a suitable vaccine to prevent EBV infection. A phase 2 trial randomized 181 healthy, EBV-seronegative young adults to receive either a placebo or recombinant EBV subunit glycoprotein 350 (gp350) vaccine in a 3-dose regimen. The vaccine targets gp350, a viral protein located on the EBV capsid that allows the virus to enter B cells, by attaching to CD21 antigens located on the surface of B cells.¹⁸ Results showed that the vaccine was effective in preventing the development of IM but did not offer increased protection against asymptomatic EBV infection. The study did not address the risk of developing complications and malignancies associated with IM.¹⁸ The vaccine is safe and well-tolerated. A superior vaccine would incorporate T-cell target antigens. This would help T cells to recognize and destroy infected B cells, which remain infected for life, leading to a chronic carrier state.⁴ The development of a vaccine is clinically feasible to prevent IM and urgently needed since many serious malignancies are associated with EBV infection.

CONCLUSION

Because EBV is highly contagious and is linked to numerous complications, malignancies, and death, clinicians must be familiar with risks for transmission and other possible etiologies. Serologic testing is vital to diagnosis. PAs who remain alert to the possibility of infection with EBV can help to prevent unnecessary complications and improve the prognosis of those infected with this disease.