DR.SHABNAM TEHRANI INFECTIOUS DISEASE SPECIALIST SHAHID BEHESHTI UNIVERSITY OF MEDICAL SCIENCES Infectious Mononucleosis

Definition The virus is a member of the family Herpesviridae. Epstein-Barr virus (EBV) is the cause of heterophile- positive infectious mononucleosis (IM) which is characterized by fever, sore throat, lymphadenopathy, and atypical lymphocytosis. EBV is also associated with several human tumors, including nasopharyngeal carcinoma, Burkitt's lymphoma, Hodgkin's disease, and (in patients with immunodeficiencies) B cell lymphoma.

Epidemiology EBV infections occur worldwide. These infections are most common in early childhood, with a second peak during late adolescence By adulthood, more than 90% of individuals have been infected and have antibodies to the virus.

In lower socioeconomic groups and in areas of the world with deficient standards of hygiene (e.g., developing regions), EBV tends to infect children at an early age, and IM is uncommon. In areas with higher standards of hygiene, infection with EBV is often delayed until adulthood, and IM is more prevalent.

… EBV is spread by contact with oral secretions. The virus is frequently transmitted from asymptomatic adults to infants and among young adults by transfer of saliva during kissing. More than 90% of asymptomatic seropositive individuals shed the virus in oropharyngeal secretions EBV has been transmitted by blood transfusion and by bone marrow transplantation.(rare)

Pathogenesis EBV is transmitted by salivary secretions. The virus infects the epithelium of the oropharynx and the salivary glands and is shed from these cells The proliferation and expansion of EBV-infected B cells along with reactive T cells during IM result in enlargement of lymphoid tissue. Cellular immunity is more important than humoral immunity in controlling EBV infection

Clinical Manifestations Signs and Symptoms: -Most EBV infections in infants and young children either are asymptomatic or present as mild pharyngitis with or without tonsillitis. -up to 75% of infections in adolescents present as IM. -IM in the elderly presents relatively often as nonspecific symptoms, including prolonged fever, fatigue, myalgia, and malaise.

pharyngitis, lymphadenopathy, splenomegaly, and atypical lymphocytes are relatively rare in elderly patients incubation period: in young adults is 4–6 weeks.

… A prodrome of fatigue, malaise, and myalgia may last for 1–2 weeks before the onset of fever, sore throat, and lymphadenopathy. Fever is usually low-grade and is most common in the first 2 weeks of the illness; however, it may persist for >1 month.

Signs Lymphadenopathy % 95 Fever %93 Pharyngitis or tonsillitis %82 Splenomegaly %51 Hepatomegaly %11 Rash %10 Periorbital edema %13 Palatal enanthem %7 Jaundice %5

… Lymphadenopathy and pharyngitis are most prominent during the first 2 weeks of the illness splenomegaly is more prominent during the second and third weeks. Lymphadenopathy most often affects the posterior cervical nodes but may be generalized. Enlarged lymph nodes are frequently tender and symmetric but are not fixed.

… Pharyngitis, often the most prominent sign, can be accompanied by enlargement of the tonsils with an exudate resembling that of streptococcal pharyngitis. A morbilliform or papular rash, usually on the arms or trunk, develops in 5% of cases. Most patients treated with ampicillin develop a macular rash; this rash is not predictive of future adverse reactions to penicillins

…

… Most patients have symptoms for 2–4 weeks. malaise and difficulty concentrating can persist for months

Laboratory Findings white blood cell count is usually elevated and peaks at 10,000–20,000 during the second or third week of illness. Lymphocytosis is usually demonstrable, with >10% atypical lymphocytes atypical lymphocytes are enlarged lymphocytes that have abundant cytoplasm, vacuoles, and indentations of the cell membrane

atypical lymphocyte

… Low-grade neutropenia and thrombocytopenia are common during the first month of illness. Liver function is abnormal in >90% of cases. Serum levels of aminotransferases and alkaline phosphatase are usually mildly elevated. The serum concentration of bilirubin is elevated in ~40% of cases.

Complications Most cases of IM are self-limited. Deaths are very rare and most often are due to: central nervous system (CNS) complications, splenic rupture, upper airway obstruction, or bacterial superinfection

CNS complications:  develop usually do so during the first 2 weeks of EBV infection.  Meningitis and encephalitis are the most common neurologic abnormalities, and patients may present with headache, meningismus, or cerebellar ataxia

… Autoimmune hemolytic anemia:  occurs in 2% of cases during the first 2 weeks.  In most cases, the anemia is Coombs-positive, with cold agglutinins directed against the red blood cell antigen. spleen ruptures:  in <0.5% of cases which is more common among male than female patients  may manifest as abdominal pain, referred shoulder pain, or hemodynamic compromise

Hypertrophy of lymphoid tissue in the tonsils or adenoids: can result in upper airway obstruction.

… Other rare complications associated with acute EBV infection include: o hepatitis (which can be fulminant) o myocarditis or pericarditis o pneumonia with pleural effusion o interstitial nephritis o vasculitis.

Diagnosis heterophile test : -human serum is absorbed with guinea pig kidney, and the heterophile titer is defined as the greatest serum dilution that agglutinates sheep, horse, or cow erythrocytes. -Tests for heterophile antibodies are positive in 40% of patients with IM during the first week of illness and in 80–90% during the third week.

-Therefore, repeated testing may be necessary, especially if the initial test is performed early. These antibodies usually are not detectable in children <5 years of age, in the elderly, or in patients presenting with symptoms not typical of IM

monospot test: The commercially available monospot test for heterophile antibodies is somewhat more sensitive than the classic heterophile test. The monospot test is 75% sensitive and 90% specific compared with EBV-specific serologies

… EBV-specific antibody testing : used for patients with suspected acute EBV infection who lack heterophile antibodies and for patients with atypical infections. Anti-VCA IgM and IgG antibodies : - elevated in the serum of more than 90% of patients at the onset of disease

- Anti-VCA IgM :diagnosis of acute IM because it is present at elevated titers only during the first 2–3 months of the disease - Anti-VCA IgG usually not useful for diagnosis of IM but is often used to assess past exposure to EBV because it persists for life

Seroconversion to EBNA positivity : is also useful for the diagnosis of acute infection with EBV. Antibodies to EBNA become detectable relatively late (3–6 weeks after the onset of symptoms) in nearly all cases of acute EBV infection and persist for the lifetime of the patient.

Differential Diagnosis CMV HIV Toxoplasmosis HHV-6 Streptococcal pharyngitis Viral hepatitis Rubella Lymphoma Drugs (phenytoin, carbamazepine, sulfonamides, or minocycline)

Treatment Therapy for IM consists of supportive measures, with rest and analgesia Excessive physical activity during the first month should be avoided to reduce the possibility of splenic rupture Acyclovir has had no significant clinical impact on IM in controlled trials. Glucocorticoid therapy is not indicated for uncomplicated IM and in fact may predispose to bacterial superinfection

Glucocorticoid therapy: prevention of airway obstruction in patients with severe tonsillar hypertrophy autoimmune hemolytic anemia hemophagocytic lymphohistiocytosis severe thrombocytopenia Glucocorticoid therapy have also been administered to rare patients with severe malaise and fever & to patients with severe CNS or cardiac disease. Glucocorticoid therapy have also been administered to rare patients with severe malaise and fever & to patients with severe CNS or cardiac disease.

Prevention The isolation of patients with IM is unnecessary.